Wikipedia

TAAR1

Trace amine-associated receptor 1(TAAR1) is atrace amine-associated receptor(TAAR)proteinthat in humans is encoded by theTAAR1gene.[5]

TAAR1
Identifiers
AliasesTAAR1,TA1, TAR1, TRAR1, trace amine associated receptor 1, Trace amine receptor
External IDsOMIM:609333;MGI:2148258;HomoloGene:24938;GeneCards:TAAR1;OMA:TAAR1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

134864

111174

Ensembl

ENSG00000146399

ENSMUSG00000056379

UniProt

Q96RJ0

Q923Y8

RefSeq (mRNA)

NM_138327

NM_053205

RefSeq (protein)

NP_612200

NP_444435

Location (UCSC)Chr 6: 132.64 – 132.66 MbChr 10: 23.8 – 23.8 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TAAR1 is a primarilyintracellularamine-activatedGs-coupledandGq-coupledG protein-coupled receptor(GPCR) that is primarily expressed in several peripheral organs and cells (e.g., thestomach,small intestine,duodenum,andwhite blood cells),astrocytes,and in theintracellular milieuwithin the presynapticplasma membrane(i.e.,axon terminal) ofmonoamineneuronsin thecentral nervous system(CNS).[6][7][8][9]

TAAR1 is one of six functional human TAARs, which are so named for their ability to bindendogenousamines that occur in tissues at trace concentrations.[10][11]TAAR1 plays a significant role in regulatingneurotransmissionindopamine,norepinephrine,andserotoninneurons in the CNS;[12][13][7][10]it also affectsimmune systemandneuroimmune systemfunction through different mechanisms.[14][15][16][17]

Endogenousligandsof the TAAR1 include trace amines,monoamine neurotransmitters,and certainthyronamines.[18][6]The trace aminesβ-phenethylamine,tyramine,tryptamine,andoctopamine,the monoamine neurotransmitters dopamine and serotonin, and the thyronamine3-iodothyronamine(3-IT) are all agonists of the TAAR1 in different species.[18][6][19]Other endogenous agonists are also known.[18]A variety ofexogenouscompoundsanddrugsare TAAR1 agonists as well, including variousphenethylamines,amphetamines,tryptamines,andergolines,among others.[18]There are marked species differences in the interactions of ligands with the TAAR1, resulting in greatly differingaffinities,potencies,andefficaciesof TAAR1 ligands between species.[18]Many compounds that are TAAR1 agonists in rodents are much less potent or inactive at the TAAR1 in humans.[18]

A number ofselectiveTAAR1 ligands have been developed, for instance the TAAR1full agonistRO5256390,the TAAR1partial agonistRO5263397,and the TAAR1antagonistsEPPTBandRTI-7470-44.[18][20]Selective TAAR1 agonists are used inscientific research,and a few TAAR1 agonists, such asulotarontandralmitaront,are being developed as novelpharmaceutical drugs,for instance to treatschizophreniaandsubstance use disorder.[20][21][22]

The TAAR1 was discovered in 2001 by two independent groups, Borowskiet al.and Bunzowet al.[19][23]

Discovery

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TAAR1 was discovered independently by Borowskiet al.and Bunzowet al.in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures ofoligonucleotideswith sequences related toG protein-coupled receptors(GPCRs) ofserotoninanddopamineto discover novelDNA sequencesinratgenomicDNAandcDNA,which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.[19][23]Further characterization of the functional role of TAAR1 and other receptors from this family was performed by other researchers includingRaul Gainetdinovand his colleagues.[18]

Structure

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TAAR1 shares structural similarities with theclass A rhodopsinGPCRsubfamily.[23]It has 7transmembrane domainswith shortNandC terminalextensions.[24]TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAARsubfamilyhas recentlyevolved;while at the same time, the low degree of similarity between TAAR1orthologuessuggests that they are rapidly evolving.[19]TAAR1 shares a predictivepeptidemotifwith all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues haveligandpocket vectors that utilize sets of 35amino acidsknown to be involved directly in receptor-ligand interaction.[11]

Gene

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All human TAAR genes are located on a singlechromosomespanning 109 kb ofhumanchromosome 6q23.1, 192 kb ofmousechromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a singleexon,except forTAAR2,which is coded by two exons.[11]The humanTAAR1gene is thought to be anintronlessgene.[25]

Tissue distribution

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This diagram illustrates how TAAR1 activation inducesincretin-like effects through the release of gastrointestinal hormones and influences food intake,blood glucoselevels, andinsulinrelease.[9]TAAR1 expression in the periphery is indicated with "x".[9]

To date, TAAR1 has been identified and cloned in five differentmammalgenomes:human, mouse, rat,monkey,andchimpanzee.In rats,mRNAfor TAAR1 is found at low to moderate levels in peripheral tissues like thestomach,kidney,intestines[26]andlungs,and at low levels in thebrain.[19]Rhesus monkeyTaar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of bothspecies.These regions include the dorsal and ventralcaudate nucleus,putamen,substantia nigra,nucleus accumbens,ventral tegmental area,locus coeruleus,amygdala, andraphe nucleus.[6][27]hTAAR1 has also been identified in human astrocytes.[6][14]

Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in thestomach,intestines,[26]duodenum,[26]pancreaticβ-cells,andwhite blood cells.[9][26]In the duodenum, TAAR1 activation increasesglucagon-likepeptide-1(GLP-1) andpeptide YY(PYY) release;[9]in the stomach, hTAAR1 activation has been observed to increasesomatostatin(growthhormone-inhibitinghormone) secretion fromdelta cells.[9]

hTAAR1 is the onlyhuman trace amine-associated receptorsubtype that is not expressed within the humanolfactory epithelium.[28]

Location within neurons

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TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals.[7][10][29]In model cell systems, hTAAR1 has extremely poor membrane expression.[29]A method to induce hTAAR1 membrane expression has been used to study its pharmacology via abioluminescence resonance energy transfercAMP assay.[29]

Because TAAR1 is an intracellular receptor in monoamine neurons,exogenousTAAR1 ligands must enter the presynaptic neuron through amembrane transport protein[note 1]or be able to diffuse across the presynaptic membrane in order to reach the receptor and producereuptake inhibitionandneurotransmitter efflux.[10]Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron.[10]The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons.[10]E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce –all else equal– markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.

TAAR1 ligands have also been found to enter neurons by transporters other than the monoamine transporters.[30][31][32]

Receptor oligomers

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TAAR1 formsGPCR oligomerswith monoamine autoreceptors in neuronsin vivo.[31][33]These and other reported TAAR1 hetero-oligomers include:

[note 2] in the TAAR1- D2sh example shows that TAAR1 can be located at cell membranes, and in the case of enterochromaffin cells in the gut epithelium, TAAR1 can be activated by high doses of dietary 'trace' amines, proximal to vesicles packed with catecholamines, impacting the vagal nerve system and CNS. This raises questions about where T1AM might find TAAR1 and cause similar unexpected nerve firing.

Ligands

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Trace amine-associated receptor 1
Transduction mechanismsGs,Gq,GIRKs,β-arrestin 2
Primaryendogenous agonistsTyramine,β-phenylethylamine,octopamine,dopamine
AgonistsFull agonists:RO5166017,RO5256390,ulotaront,amphetamine,methamphetamine
Partial agonists:RO5203648,RO5263397,RO5073012,ralmitaront
Neutral antagonistsRTI-7470-44
Inverse agonistsEPPTB
Positive allosteric modulatorsNone known
Negative allosteric modulatorsNone known
External resources
IUPHAR/BPS364
DrugBankQ96RJ0
HMDBHMDBP10805

Agonists

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Endogenous

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For a more comprehensive list, seeTrace amine § List of trace amines.

The knownendogenousagonistsof the TAAR1 includetrace amineslikeβ-phenethylamine(PEA),monoamine neurotransmitterslikedopamine,andthyronamineslike3-iodothyronamine(T1AM).[12]

Trace aminesare endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10nM in the brain, constituting less than 1% of total biogenic amines in the mammaliannervous system.[35]Some of the human trace amines includetryptamine,phenethylamine(PEA),N-methylphenethylamine,p-tyramine,m-tyramine,N-methyltyramine,p-octopamine,m-octopamine,andsynephrine.These share structural similarities with the three commonmonoamine neurotransmitters:serotonin,dopamine,andnorepinephrine.Each ligand has a different potency, measured as increasedcyclic AMP(cAMP) concentration after the binding event. The rank order of potency for the primary endogenous ligands at the human TAAR1 is:tyramine>β-phenethylamine>dopamine=octopamine.[6][19]Tryptamineandhistaminealso interact with the human TAAR1 with lower potency, whereasserotoninandnorepinephrinehave been found to be inactive.[18][19][36][23]

Thyronaminesare molecular derivatives ofthyroid hormoneinvolved inendocrine systemfunction.3-Iodothyronamine(T1AM) is one of the most potent TAAR1 agonists yet discovered. It also interacts with a number of othertargets.[13][37][38]Unlike the monoamine neurotransmitters and trace amines, T1A is not amonoamine transporter(MAT)substrate,although it does still weakly interact with the MATs.[37][39]Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreasedbody temperatureandcardiac output.

Other endogenous TAAR1 agonists includecyclohexylamine,isoamylamine,andtrimethylamine,among others.[18][22][40]

Exogenous

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Although amphetamine, methamphetamine, and MDMA arepotentTAAR1 agonists in rodents, they are much less potent in terms of TAAR1 agonism in humans.[18][65][36][66]As examples, whereas amphetamine and methamphetamine havenanomolarpotencies in activating the TAAR1 in rodents, they havemicromolarpotencies for TAAR1 agonism in humans.[18][65][36][42][66]MDMA shows very weak potency and efficacy as a human TAAR1 agonist and has been regarded as inactive.[18][65][36][67]Relatedly, it is not entirely clear whether agents like amphetamine and methamphetamine at typical doses produce significant TAAR1 agonism and associated effects in humans.[68][41][66][69]However, TAAR1 agonism and consequent effects by these drugs may be more relevant in the context of very highrecreationaldoses.[41][66]TAAR1 activation has been found to have inhibitory effects onmonoaminergicneurotransmission,and TAAR1 agonism by amphetamines may serve to auto-inhibit and constrain their effects.[70][68][71][53]

While someamphetaminesare human TAAR1 agonists, many others are not.[36]As examples, mostcathinones(β-ketoamphetamines), such asmethcathinone,mephedrone,andflephedrone,as well as other amphetamines, includingephedrine,4-methylamphetamine(4-MA),para-chloroamphetamine(PCA),[53]para-methoxyamphetamine(PMA),4-methylthioamphetamine(4-MTA),MDEA,MBDB,5-APDB,and5-MAPDB,are inactive as human TAAR1 agonists.[68][36]Many other drugs acting asmonoamine releasing agents(MRAs) are also inactive as human TAAR1 agonists, for instancepiperazineslikebenzylpiperazine(BZP),meta-chlorophenylpiperazine(mCPP), and3-trifluoromethylphenylpiperazine(TFMPP), as well as thealkylaminemethylhexanamine(DMAA).[18][36][72]The negligible TAAR1 agonism with most cathinones might serve to enhance their effects andmisuse potentialas MRAs compared to their amphetamine counterparts.[68][71]

Monoaminergic activity enhancers(MAEs), such asselegiline,benzofuranylpropylaminopentane(BPAP), andphenylpropylaminopentane(PPAP), have been claimed to act as TAAR1 agonists to mediate their MAE effects, but TAAR1 agonism for BPAP and PPAP has yet to be assessed or confirmed.[73][74]Selegiline is only a weak agonist of the mouse TAAR1, with dramatically lower potency thanamphetamineormethamphetamine,and does not seem to have been assessed at the human TAAR1.[44][74]

Antagonists and inverse agonists

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A few other less well-known TAAR1 antagonists have also been discovered and characterized.[80][76][81][79]

RO5073012is an antagonist-esque weak partial agonist of the rodent and human TAAR1 (EmaxTooltip maximal efficacy= 24–35%).[18][61][82][83]Similarly,MDAandMDMAare weak to very weakpartial agonistsor antagonists of the human TAAR1 (Emax= 11% and 26%, respectively), albeit with very lowpotency.[18][36][42]

It has been claimed thatrasagilinemay act as a TAAR1 antagonist, but TAAR1 interactions have yet to be assessed or confirmed for this agent.[74]

Function

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Phenethylamine and amphetamine in a TAAR1-localized dopamine neuron
viaAADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or throughDAT.[10]Once inside, it binds toTAAR1or enters synaptic vesicles throughVMAT2.[10][84][85]When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into thecytosol(light tan-colored area) through VMAT2.[84][86]When amphetamine binds to TAAR1, it reduces thefiring rateof the dopamine neuron viaG protein-coupled inwardly rectifying potassium channels(GIRKs) and activatesprotein kinase A(PKA) andprotein kinase C(PKC), which subsequently phosphorylate DAT.[10][87][88]PKA phosphorylationcauses DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[10]PKC-phosphorylatedDAT may either operate in reverse or, likePKA-phosphorylatedDAT, internalize and cease transport.[10][85]Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through aCAMKIIα-dependent pathway, in turn producing dopamine efflux.[89][90]


Monoaminergic systems

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Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release fromsympathetic nerve endingsand compete forcatecholamineor serotonin binding sites on cognate receptors, transporters, and storage sites.[35]Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.

One of the downstream effects of active TAAR1 is to increasecAMPin the presynapticcellvia GαsG-protein activation ofadenylyl cyclase.[19][23][11]This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cellcytoplasm.[91]These amines would then activate intracellular TAAR1. Monoamineautoreceptors(e.g.,D2short,presynaptic α2,andpresynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[10]Notably,amphetamineand trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[10][7]The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[10]Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1co-localizationin the associated monoamine neurons.[10]As of 2010,co-localizationof TAAR1 and thedopamine transporter(DAT) has been visualized in rhesus monkeys, butco-localizationof TAAR1 with thenorepinephrine transporter(NET) and theserotonin transporter(SERT) has only been evidenced bymessenger RNA(mRNA) expression.[10]

In neurons withco-localizedTAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in thesynaptic cleft,thereby increasing post-synaptic receptor binding.[10]Through direct activation ofG protein-coupled inwardly-rectifying potassium channels(GIRKs), TAAR1 can reduce thefiring rateof dopamine neurons, in turn preventing a hyper-dopaminergic state.[54][87][88]Amphetamine and trace amines can enter thepresynaptic neuroneither throughDATor by diffusing across the neuronal membrane directly.[10]As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[10]Upon entering the presynaptic neuron, these compounds activate TAAR1 which, throughprotein kinase A(PKA) andprotein kinase C(PKC) signaling, causes DATphosphorylation.Phosphorylation by either protein kinase can result in DATinternalization(non-competitivereuptake inhibition), butPKC-mediatedphosphorylation alone induces reverse transporter function (dopamineefflux).[10][92]

Immune system

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See also:Neuroimmune system

Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics.[16]In the immune system, TAAR1 transmits signals through active PKA and PKCphosphorylationcascades.[16]In a 2012 study, Panaset al.observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system.[16]A recent paper showed that, along with TAAR1,TAAR2is required for full activity of trace amines inPMN cells.[17]

PhytohaemagglutininupregulateshTAAR1mRNAin circulatingleukocytes;[6]in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists.[6]TAAR1 agonists (specifically, trace amines) have also been shown to induceinterleukin 4secretion inT-cellsandimmunoglobulin E(IgE) secretion inB cells.[6]

Astrocyte-localized TAAR1 regulatesEAAT2levels and function in these cells;[14]this has been implicated in methamphetamine-induced pathologies of theneuroimmune system.[14]

Clinical significance

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Lowphenethylamine(PEA) concentration in the brain is associated withmajor depressive disorder,[19][35][93]and high concentrations are associated withschizophrenia.[93][94]Low PEA levels and under-activation of TAAR1 also appears to be associated withADHD.[93][94][95]It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression.[19][35]Some antidepressants function by inhibitingmonoamine oxidase(MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells.[19][11]Decreased PEAmetabolismhas been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function.Mutationsin region q23.1 ofhuman chromosome 6– the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[11]

Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.).[7][8]Despite wide distribution outside of the CNS and PNS, TAAR1 does not affect hematological functions and the regulation of thyroid hormones across different stages of ageing. Such data represent that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile.[96]

Research

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A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this possibly presents a target for therapeutic intervention.[97]

In preclinical research on rats, TAAR1 activation in pancreatic cells promotesinsulin,peptide YY,andGLP-1secretion;[98][non-primary source needed]therefore, TAAR1 is potentially a biological target for the treatment ofobesityanddiabetes.[98][non-primary source needed]

Lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.[99]

See also

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Notes

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  1. ^Indopamine,norepinephrine,andserotoninneurons, the primary membrane transporters areDAT,NET,andSERTrespectively.[10]
  2. ^TAAR1–D2sh is a presynapticheterodimerwhich involves the relocation of TAAR1 from the intracellular space to D2sh at theplasma membrane,increased D2sh agonistbinding affinity,andsignal transductionthrough the calcium–PKC–NFATpathway andG-proteinindependentPKB–GSK3pathway.[7][34]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000146399–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000056379–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Entrez Gene: TAAR1 trace amine associated receptor 1".
  6. ^abcdefghijMaguire JJ, Davenport AP (20 February 2018)."Trace amine receptor: TA1receptor ".IUPHAR/BPS Guide to PHARMACOLOGY.International Union of Basic and Clinical Pharmacology.Retrieved16 July2018.
    Tissue Distribution
    CNS (region specific) & several peripheral tissues:
    Stomach > amygdala, kidney, lung, small intestine > cerebellum, dorsal root ganglion, hippocampus, hypothalamus, liver, medulla oblongata, pancreas, pituitary gland, pontine reticular formation, prostate, skeletal muscle, spleen....
    Leukocytes...Pancreatic islet β cells... Primary Tonsillar B Cells... Circulating leukocytes of healthy subjects (upregulation occurs upon addition of phytohaemagglutinin).
    Species: Human...
    In the brain (mouse, rhesus monkey) the TA1 receptor localises to neurones within the momaminergic pathways and there is emerging evidence for a modulatory role for TA1 on function of these systems. Co-expression of TA1 with the dopamine transporter (either within the same neurone or in adjacent neurones) implies direct/indirect modulation of CNS dopaminergic function. In cells expressing both human TA1 and a monoamine transporter (DAT, SERT or NET) signalling via TA1 is enhanced [26,48,50–51]....
    Functional Assays...
    Mobilization of internal calcium in RD-HGA16 cells transfected with unmodified human TA1
    Response measured: Increase in cytopasmic calcium...
    Measurement of cAMP levels in human cultured astrocytes.
    Response measured: cAMP accumulation...
    Activation of leukocytes
    Species: Human
    Tissue: PMN, T and B cells
    Response measured: Chemotactic migration towards TA1 ligands (β-Phenylethylamine, tyramine and 3-iodothyronamine), trace amine induced IL-4 secretion (T-cells) and trace amine induced regulation of T cell marker RNA expression, trace amine induced IgE secretion in B cells.
  7. ^abcdefghGrandy DK, Miller GM, Li JX (February 2016).""TAARgeting Addiction" -The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference ".Drug Alcohol Depend.159:9–16.doi:10.1016/j.drugalcdep.2015.11.014.PMC4724540.PMID26644139.TAAR1 is a high-affinity receptor for METH/AMPH and DA... This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
  8. ^abJing L, Li JX (August 2015)."Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction".Eur. J. Pharmacol.761:345–352.doi:10.1016/j.ejphar.2015.06.019.PMC4532615.PMID26092759.TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)... Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010).
  9. ^abcdefghiBerry MD, Gainetdinov RR, Hoener MC, Shahid M (December 2017)."Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges".Pharmacology & Therapeutics.180:161–180.doi:10.1016/j.pharmthera.2017.07.002.PMID28723415.
  10. ^abcdefghijklmnopqrstuMiller GM (January 2011)."The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity".Journal of Neurochemistry.116(2):164–176.doi:10.1111/j.1471-4159.2010.07109.x.PMC3005101.PMID21073468.
  11. ^abcdefLindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC (March 2005). "Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors".Genomics.85(3):372–385.doi:10.1016/j.ygeno.2004.11.010.PMID15718104.
  12. ^abcdefghijkPei Y, Asif-Malik A, Canales JJ (2016)."Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications".Front Neurosci.10:148.doi:10.3389/fnins.2016.00148.PMC4820462.PMID27092049.
  13. ^abRutigliano G, Accorroni A, Zucchi R (2017)."The Case for TAAR1 as a Modulator of Central Nervous System Function".Front Pharmacol.8:987.doi:10.3389/fphar.2017.00987.PMC5767590.PMID29375386.T1AM has been reported to be a multitarget ligand, since it can also interact with other TAAR subtypes (particularly TAAR5), α2A- and β-adrenergic receptors, TRM8 calcium channels, and membrane amine transporters like dopamine transporter (DAT), norepinephrine transporter (NET), and vesicular monoamine transporter (VMAT) (reviewed by Hoefig et al., 2016). The affinity for these additional targets is substantially lower than the affinity for rat TAAR1, but the difficulties in assessing T1AM concentration at receptor level do not enable to reach a clear conclusion about their physiological relevance. As discussed below, the presence of non-TAAR targets is an important pitfall in the interpretation of experimental results obtained with the administration of natural TAAR1 ligands.
  14. ^abcdCisneros IE, Ghorpade A (October 2014)."Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes".Neuropharmacology.85:499–507.doi:10.1016/j.neuropharm.2014.06.011.PMC4315503.PMID24950453.TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
  15. ^Rogers TJ (2012)."The molecular basis for neuroimmune receptor signaling".J Neuroimmune Pharmacol.7(4):722–724.doi:10.1007/s11481-012-9398-4.PMC4011130.PMID22935971.
  16. ^abcdPanas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM (December 2012)."Trace amine associated receptor 1 signaling in activated lymphocytes".Journal of Neuroimmune Pharmacology.7(4):866–876.doi:10.1007/s11481-011-9321-4.PMC3593117.PMID22038157.
  17. ^abBabusyte A, Kotthoff M, Fiedler J, Krautwurst D (March 2013). "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2".Journal of Leukocyte Biology.93(3):387–394.doi:10.1189/jlb.0912433.PMID23315425.S2CID206996784.
  18. ^abcdefghijklmnopqrstuvwxyzaaabacadaeafagahaiajakalamanaoapGainetdinov RR, Hoener MC, Berry MD (July 2018)."Trace Amines and Their Receptors".Pharmacol Rev.70(3):549–620.doi:10.1124/pr.117.015305.PMID29941461.
  19. ^abcdefghijkBorowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. (July 2001)."Trace amines: identification of a family of mammalian G protein-coupled receptors".Proceedings of the National Academy of Sciences of the United States of America.98(16):8966–8971.Bibcode:2001PNAS...98.8966B.doi:10.1073/pnas.151105198.PMC55357.PMID11459929.
  20. ^abSchwartz MD, Canales JJ, Zucchi R, Espinoza S, Sukhanov I, Gainetdinov RR (June 2018). "Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases".Expert Opin Ther Targets.22(6):513–526.doi:10.1080/14728222.2018.1480723.hdl:11568/930006.PMID29798691.
  21. ^Liu J, Wu R, Li JX (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders".Pharmacol Ther.253:108580.doi:10.1016/j.pharmthera.2023.108580.PMID38142862.
  22. ^abcdefgShajan B, Bastiampillai T, Hellyer SD, Nair PC (2024)."Unlocking the secrets of trace amine-associated receptor 1 agonists: new horizon in neuropsychiatric treatment".Front Psychiatry.15:1464550.doi:10.3389/fpsyt.2024.1464550.PMC11565220.PMID39553890.
  23. ^abcdefghijklmnopqrstuvwxBunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor".Molecular Pharmacology.60(6):1181–1188.doi:10.1124/mol.60.6.1181.PMID11723224.
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  27. ^Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, et al. (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro".The Journal of Pharmacology and Experimental Therapeutics.321(1):116–127.doi:10.1124/jpet.106.116863.PMID17234900.S2CID578835.
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  29. ^abcBarak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, et al. (September 2008)."Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor".Molecular Pharmacology.74(3):585–594.doi:10.1124/mol.108.048884.PMC3766527.PMID18524885.
  30. ^Wu R, Liu J, Li JX (2022). "Trace amine-associated receptor 1 and drug abuse".Behavioral Pharmacology of Drug Abuse: Current Status.Adv Pharmacol. Vol. 93. pp.373–401.doi:10.1016/bs.apha.2021.10.005.ISBN978-0-323-91526-7.PMC9826737.PMID35341572.A more recent study suggested that trace amines action is dependent on intracellular uptake by pentamidine-sensitive Na(+)-independent membrane transporters but not monoamine transporters (Gozal et al., 2014). Gozal EA, O'Neill BE, Sawchuk MA, Zhu H, Halder M, Chou CC, & Hochman S (2014). Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord. Front Neural Circuits, 8, 134. doi: 10.3389/fncir.2014.00134
  31. ^abcdeLam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1".Eur. J. Pharmacol.763(Pt B):136–42.doi:10.1016/j.ejphar.2015.06.026.PMID26093041.
    TAAR1 peripheral and immune localization/functions: It is important to note that in addition to the brain, TAAR1 is also expressed in the spinal cord (Gozal et al., 2014) and periphery (Revel et al., 2012c). It has been shown that TAAR1 is expressed and regulates immune function in rhesus monkey leukocytes (Babusyte et al., 2013; Nelson et al., 2007; Panas et al., 2012). In granulocytes, TAAR1 is necessary for chemotaxic migration of cells towards TAAR1 agonists. In addition, TAAR1 signaling in B and T cells can trigger immunoglobulin and cytokine release, respectively (Babusyte et al., 2013). TAAR1 is also expressed in the islets of Langerhans, stomach and intestines based on LacZ staining patterns carried out on TAAR1-KO LacZ mice (Revel et al., 2012c). Interestingly, the administration of selective TAAR1 partial agonist RO5263397 reverses the side effect of weight gain observed with the antipsychotic olanzapine, indicating that peripheral TAAR1 signalling can regulate metabolic homeostasis (Revel et al., 2012b)....

    Monoamine transporters and SLC22A carrier subfamily transport TAAR1 ligand: Studies using the rhesus monkey TAAR1 have shown that this receptor interacts with the monoamine transporters DAT, SERT, and NET in HEK cells (Miller et al., 2005; Xie and Miller, 2007; Xie et al., 2007). It has been hypothesized that TAAR1 interaction with these transporters might provide a mechanism by which TAAR1 ligands can enter the cytoplasm and bind to TAAR1 in intracellular compartments. A recent study has shown that in rat neonatal motor neurons, trace-amine specific signalling requires the presence and function of the transmembrane solute carrier SLC22A but not that of monoamine transporters (DAT, SERT, and NET) (Gozal et al., 2014). Specifically, it was shown that addition of β-PEA, tyramine, or tryptamine induced locomotor like activity (LLA) firing patterns of these neurons in the presence of N-Methyl D-Aspartate. Temporally, it was found that the trace amine induction of LLA is delayed compared to serotonin and norepinephrine induced LLA, indicating the target site for the trace amines is not located on the plasma membrane and could perhaps be intracellular. Importantly, blocking of SLC22A with pentamidine abolished trace amine induced LLA, indicating that trace amine induced LLA does not act on receptors found on the plasma membrane but requires their transport to the cytosol by SLC22A for induction of LLA.
  32. ^Gozal EA, O'Neill BE, Sawchuk MA, Zhu H, Halder M, Chou CC, et al. (2014)."Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord".Front Neural Circuits.8:134.doi:10.3389/fncir.2014.00134.PMC4224135.PMID25426030.TA actions on locomotor circuits did not require interaction with descending monoaminergic projections since evoked LLA was maintained following block of all Na(+)-dependent monoamine transporters or the vesicular monoamine transporter. Instead, TA (tryptamine and tyramine) actions depended on intracellular uptake via pentamidine-sensitive Na(+)-independent membrane transporters. Requirement for intracellular transport is consistent with the TAs having much slower LLA onset than serotonin and for activation of intracellular TAARs.
  33. ^abDinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, et al. (June 2015)."3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling".J. Mol. Endocrinol.54(3):205–216.doi:10.1530/JME-15-0003.PMID25878061.Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.
  34. ^Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, et al. (2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers".Eur Neuropsychopharmacol.25(11):2049–2061.doi:10.1016/j.euroneuro.2015.08.011.PMID26372541.S2CID41667764.Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
  35. ^abcdZucchi R, Chiellini G, Scanlan TS, Grandy DK (December 2006)."Trace amine-associated receptors and their ligands".British Journal of Pharmacology.149(8):967–978.doi:10.1038/sj.bjp.0706948.PMC2014643.PMID17088868.Other biogenic amines are present in the central nervous system at very low concentrations in the order of 0.1–10 nm, representing <1% of total biogenic amines (Berry, 2004). For these compounds, the term 'trace amines' was introduced. Although somewhat loosely defined, the molecules generally considered to be trace amines include para-tyramine, meta-tyramine, tryptamine, β-phenylethylamine, para-octopamine and meta-octopamine (Berry, 2004) (Figure 2).
  36. ^abcdefghijklmnopqrSimmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1".J Pharmacol Exp Ther.357(1):134–144.doi:10.1124/jpet.115.229765.PMID26791601.
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  38. ^Biebermann H, Kleinau G (June 2020). "3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors".Exp Clin Endocrinol Diabetes.128(6–07):395–400.doi:10.1055/a-1022-1554.PMID31698479.
  39. ^Snead AN, Santos MS, Seal RP, Miyakawa M, Edwards RH, Scanlan TS (June 2007). "Thyronamines inhibit plasma membrane and vesicular monoamine transport".ACS Chem Biol.2(6):390–398.doi:10.1021/cb700057b.PMID17530732.
  40. ^Xu Z, Guo L, Yu J, Shen S, Wu C, Zhang W, et al. (December 2023). "Ligand recognition and G-protein coupling of trace amine receptor TAAR1".Nature.624(7992):672–681.Bibcode:2023Natur.624..672X.doi:10.1038/s41586-023-06804-z.PMID37935376.
  41. ^abcdefgGrandy DK (December 2007)."Trace amine-associated receptor 1-Family archetype or iconoclast?".Pharmacol Ther.116(3):355–390.doi:10.1016/j.pharmthera.2007.06.007.PMC2767338.PMID17888514.[AMPH and METH] promote DA release from synaptic storage vesicles into the cytoplasm (Partilla et al., 2006) and then into the extracellular space via DAT with an EC50 of 25 nM and a Ki uptake in rat synaptosomes of 34 nM (Rothman et al., 2001). These are drug concentrations approximately 20-30 fold lower than the EC50 values Reese et al. (2007) calculated for eliciting an in vitro functional response from rTAAR1 (0.8 μM). However, experienced METH users can typically consume gram quantities of drug per day (Kramer et al., 1967) and achieve peak blood concentrations of 100 μM (Derlet et al., 1989; Baselt, 2002; Peters et al., 2003). [...] The extracellular free concentration of METH surrounding relevant human dopaminergic synapses in the brain presumably is the relevant pharmacodynamic parameter, at least in part, underlying the desirable effects of the drug. Although this value is not known with certainty for humans METH serum levels typically represent one tenth of what is found in rat brain (Riviere et al., 2000). Consequently, when considered together with the human forensic evidence the in vitro results of Reese et al. (2007) are consistent with the interpretation that in vivo the human TAAR1 is likely to be a mediator of at least some of METH's effects.
  42. ^abcdefghiLewin AH, Miller GM, Gilmour B (December 2011)."Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class".Bioorg Med Chem.19(23):7044–7048.doi:10.1016/j.bmc.2011.10.007.PMC3236098.PMID22037049.
  43. ^Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, et al. (September 2008)."Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor".Mol Pharmacol.74(3):585–594.doi:10.1124/mol.108.048884.PMC3766527.PMID18524885.
  44. ^abWolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, et al. (October 2007). "The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia".Genes Brain Behav.6(7):628–639.doi:10.1111/j.1601-183X.2006.00292.x.PMID17212650.
  45. ^Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W, et al. (2023). "Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion".CNS Spectrums.28(2): 222.doi:10.1017/S1092852923001396.ISSN1092-8529.In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity.
  46. ^Krasavin M, Peshkov AA, Lukin A, Komarova K, Vinogradova L, Smirnova D, et al. (September 2022)."Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)-N-(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders".Int J Mol Sci.23(19): 11579.doi:10.3390/ijms231911579.PMC9569940.PMID36232878.
  47. ^Sukhanov I, Espinoza S, Yakovlev DS, Hoener MC, Sotnikova TD, Gainetdinov RR (October 2014). "TAAR1-dependent effects of apomorphine in mice".Int J Neuropsychopharmacol.17(10):1683–1693.doi:10.1017/S1461145714000509.PMID24925023.
  48. ^Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, et al. (January 2007). "Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1".The Journal of Pharmacology and Experimental Therapeutics.320(1):475–485.doi:10.1124/jpet.106.112532.PMID17038507.S2CID10829497.Several series of substituted phenylethylamines were investigated for activity at the human TAAR1 (Table 2). A surprising finding was the potency of phenylethylamines with substituents at the phenyl C2 position relative to their respective C4-substituted congeners. In each case, except for the hydroxyl substituent, the C2-substituted compound had 8- to 27-fold higher potency than the C4-substituted compound. The C3-substituted compound in each homologous series was typically 2- to 5-fold less potent than the 2-substituted compound, except for the hydroxyl substituent. The most potent of the 2-substituted phenylethylamines was 2-chloro-β-PEA, followed by 2-fluoro-β-PEA, 2-bromo-β-PEA, 2-methoxy-β-PEA, 2-methyl-β-PEA, and then 2-hydroxy-β-PEA.
    The effect of β-carbon substitution on the phenylethylamine side chain was also investigated (Table 3). A β-methyl substituent was well tolerated compared with β-PEA. In fact, S-(–)-β-methyl-β-PEA was as potent as β-PEA at human TAAR1. β-Hydroxyl substitution was, however, not tolerated compared with β-PEA. In both cases of β-substitution, enantiomeric selectivity was demonstrated.
    In contrast to a methyl substitution on the β-carbon, an α-methyl substitution reduced potency by ~10-fold for d-amphetamine and 16-fold for l-amphetamine relative to β-PEA (Table 4). N-Methyl substitution was fairly well tolerated; however, N,N-dimethyl substitution was not.
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  66. ^abcdReese EA, Bunzow JR, Arttamangkul S, Sonders MS, Grandy DK (April 2007). "Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine".J Pharmacol Exp Ther.321(1):178–186.doi:10.1124/jpet.106.115402.PMID17218486.The EC50 of (+)-AMPH to release DA via DAT is 25 nM, with Ki uptake values in rat synaptosomes for this neurotransmitter of 34 nM at the DAT, concentrations approximately 20- to 30-fold lower than the EC50 values we calculated for eliciting an in vitro functional response from rTAAR1 (0.8 μM). Chronic METH abusers can typically consume gram quantities of drug per day (Kramer et al., 1967). [...] plasma concentrations of both drugs can reach into the high-micromolar range (Drummer and Odell, 2001; Baselt, 2002; Peters et al., 2003). Although the extracellular free concentration of METH around relevant human dopaminergic synapses presumably involved in producing desirable CNS effects is not known with certainty, in rats METH serum levels are typically 1/10 what is found in brain (Riviere et al., 2000). Forensic evidence indicates that experienced METH users can typically achieve peak blood concentrations of 100 μM (Baselt, 2002; Peters et al., 2003). Both isomers of METH were full agonists of h-rChTAAR1 over a range of EC50 values from 3.5 to ~15 μM, concentrations often exceeded in the blood of human METH addicts (Derlet et al., 1989). If TAAR1s, whether expressed in the CNS or periphery, are exposed to such concentrations, it is possible they could become functionally activated. [...] Given that the EC50 values for METH and AMPH activation of the h-rChTAAR1 in vitro are well below the concentrations frequently found in addicts, we suggest that TAAR1 might be a potential mediator of some of the effects of AMPH and METH in humans, including hyperthermia and stroke.
  67. ^Dunlap LE, Andrews AM, Olson DE (October 2018)."Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine"(PDF).ACS Chem Neurosci.9(10):2408–2427.doi:10.1021/acschemneuro.8b00155.PMC6197894.PMID30001118.
  68. ^abcdKuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse".Hum Psychopharmacol.38(3): e2866.doi:10.1002/hup.2866.PMID36866677.Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
  69. ^Grandy DK, Miller GM, Li JX (February 2016).""TAARgeting Addiction" --The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference ".Drug Alcohol Depend.159:9–16.doi:10.1016/j.drugalcdep.2015.11.014.PMC4724540.PMID26644139.That TAAR1 signaling is coupled to the inhibition of VTA DA neuron firing was a surprising finding. [...] earlier data suggested that TAAR1 activation leads to inhibition of DA uptake by DAT, promotion of DA efflux by DAT and DAT internalization which presumably would augment extracellular DA levels, whereas inhibition of DA neuronal firing rate would likely decrease extracellular DA levels, [...] this mismatch in expectations immediately attracted the attention of those trying to determine whether TAAR1 is a METH/AMPH and DA receptor in vivo as it is in vitro (Bunzow et al., 2001; Wainscott et al., 2007; Xie and Miller, 2009; Panas et al., 2012).
  70. ^Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1".Taste and Smell.Vol. 23. Cham: Springer International Publishing. pp.175–194.doi:10.1007/7355_2014_78.ISBN978-3-319-48925-4.Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.
  71. ^abSimmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, et al. (January 2013)."Pharmacological characterization of designer cathinones in vitro".Br J Pharmacol.168(2):458–470.doi:10.1111/j.1476-5381.2012.02145.x.PMC3572571.PMID22897747.β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines.
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  75. ^Lam VM, Mielnik CA, Baimel C, Beerepoot P, Espinoza S, Sukhanov I, et al. (2018)."Behavioral Effects of a Potential Novel TAAR1 Antagonist".Front Pharmacol.9:953.doi:10.3389/fphar.2018.00953.PMC6131539.PMID30233365.
  76. ^abLam VM, Rodríguez D, Zhang T, Koh EJ, Carlsson J, Salahpour A (2015). "Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model".MedChemComm.6(12):2216–2223.doi:10.1039/C5MD00400D.ISSN2040-2503.
  77. ^Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, et al. (November 2009)."The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system".Proceedings of the National Academy of Sciences of the United States of America.106(47):20081–20086.Bibcode:2009PNAS..10620081B.doi:10.1073/pnas.0906522106.PMC2785295.PMID19892733.
  78. ^Scarano N, Espinoza S, Brullo C, Cichero E (July 2024)."Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands".Int J Mol Sci.25(15): 8226.doi:10.3390/ijms25158226.PMC11312273.PMID39125796.On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM.
  79. ^abDecker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, et al. (April 2022)."Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist".ACS Chem Neurosci.13(7):1082–1095.doi:10.1021/acschemneuro.2c00086.PMC9730857.PMID35325532.While synthetic and endogenous hTAAR1 agonists have been developed (for a detailed review9), some with therapeutic potential for schizophrenia and substance abuse disorders,1,10–13 the discovery of TAAR1 antagonists remains surprisingly difficult. In the literature, the Hoffman-La Roche antagonist, [EPPTB], is the only fully characterized TAAR1 antagonist (Figure 1). [...] In the literature, a few additional antagonists have been identified (Cmpd 3, ET-54, ET-78),17–18 but all have weak potencies and none have been fully characterized at human, rat, and mouse TAAR1, making potency comparisons difficult (Figure 1; Cmpd 3: hTAAR1 IC50 = 9 μM, ET-54: rTAAR1 IC50 = 3 μM, ET-78: rTAAR1 IC50 = 4 μM).
  80. ^Cichero E, Espinoza S, Franchini S, Guariento S, Brasili L, Gainetdinov RR, et al. (December 2014). "Further insights into the pharmacology of the human trace amine-associated receptors: discovery of novel ligands for TAAR1 by a virtual screening approach".Chem Biol Drug Des.84(6):712–720.doi:10.1111/cbdd.12367.PMID24894156.
  81. ^Decker AM, Mathews KM, Blough BE, Gilmour BP (January 2021)."Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1".SLAS Discov.26(1):140–150.doi:10.1177/2472555220945279.PMID32734809.A few additional antagonists (Cmpd 3, ET-92, ET-78)46,47 have been identified in the literature, but none have been fully characterized and all suffer from potency issues (Cmpd 3: hTAAR1 IC50 = 9 µM, ET-92: rTAAR1 IC50 = 3 µM, ET-78: rTAAR1 IC50 = 4 µM). The discovery of our antagonists is groundbreaking, as our compounds are the most potent hTAAR1 antagonists identified to date (hTAAR1 IC50 = 206 and 281 nM).
  82. ^Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, André CB, et al. (November 2012)."Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine".Neuropsychopharmacology.37(12):2580–2592.doi:10.1038/npp.2012.109.PMC3473323.PMID22763617.
  83. ^Galley G, Stalder H, Goergler A, Hoener MC, Norcross RD (August 2012). "Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012".Bioorg Med Chem Lett.22(16):5244–5248.doi:10.1016/j.bmcl.2012.06.060.PMID22795332.
  84. ^abEiden LE, Weihe E (January 2011)."VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse".Ann. N. Y. Acad. Sci.1216(1):86–98.Bibcode:2011NYASA1216...86E.doi:10.1111/j.1749-6632.2010.05906.x.PMC4183197.PMID21272013.VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
  85. ^abQuintero J, Gutiérrez-Casares JR, Álamo C (11 August 2022)."Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review".Neurology and Therapy.11(4):1489–1517.doi:10.1007/s40120-022-00392-2.PMC9588136.PMID35951288.The active form of the drug has a central nervous system stimulating activity by the primary inhibition of DAT, NET, trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (SLC18A2), among other targets, therefore regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft....
    LDX can also promote the increase of DA in the synaptic cleft by activating protein TAAR1, which produces the efflux of monoamine NTs, mainly DA, from storage sites on presynaptic neurons. TAAR1 activation leads to intracellular cAMP signalling that results in PKA and PKC phosphorylation and activation. This PKC activation decreases DAT1, NET1 and SERT cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD.
  86. ^Sulzer D, Cragg SJ, Rice ME (August 2016)."Striatal dopamine neurotransmission: regulation of release and uptake".Basal Ganglia.6(3):123–148.doi:10.1016/j.baga.2016.02.001.PMC4850498.PMID27141430.Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle.... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
  87. ^abLedonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (2011)."Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons".Frontiers in Systems Neuroscience.5:56.doi:10.3389/fnsys.2011.00056.PMC3131148.PMID21772817.inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  88. ^abmct (28 January 2012)."TAAR1".GenAtlas.University of Paris.Retrieved29 May2014.
    "• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)"
  89. ^Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014)."Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons".Neuron.83(2):404–416.doi:10.1016/j.neuron.2014.05.043.PMC4159050.PMID25033183.AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate.... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
  90. ^Vaughan RA, Foster JD (September 2013)."Mechanisms of dopamine transporter regulation in normal and disease states".Trends Pharmacol. Sci.34(9):489–496.doi:10.1016/j.tips.2013.07.005.PMC3831354.PMID23968642.AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  91. ^Xie Z, Miller GM (July 2009)."A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain".The Journal of Pharmacology and Experimental Therapeutics.330(1):316–325.doi:10.1124/jpet.109.153775.PMC2700171.PMID19364908.
  92. ^Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP (March 2009)."International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature".Pharmacological Reviews.61(1):1–8.doi:10.1124/pr.109.001107.PMC2830119.PMID19325074.
  93. ^abcLindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family".Trends Pharmacol. Sci.26(5):274–281.doi:10.1016/j.tips.2005.03.007.PMID15860375.The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders [7,8,36]. Clinical studies report increased β-PEA plasma levels in patients suffering from acute schizophrenia [37] and elevated urinary excretion of β-PEA in paranoid schizophrenics [38], which supports a role of TAs in schizophrenia. As a result of these studies, β-PEA has been referred to as the body's 'endogenous amphetamine' [39]
  94. ^abSotnikova TD, Caron MG, Gainetdinov RR (August 2009)."Trace amine-associated receptors as emerging therapeutic targets".Mol. Pharmacol.76(2):229–235.doi:10.1124/mol.109.055970.PMC2713119.PMID19389919.Although the functional role of trace amines in mammals remains largely enigmatic, it has been noted that trace amine levels can be altered in various human disorders, including schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, and phenylketonuria (Boulton, 1980; Sandler et al., 1980). It was generally held that trace amines affect the monoamine system indirectly via interaction with plasma membrane transporters [such as plasma membrane dopamine transporter (DAT)] and vesicular storage (Premont et al., 2001; Branchek and Blackburn, 2003; Berry, 2004; Sotnikova et al., 2004)....
    Furthermore, DAT-deficient mice provide a model to investigate the inhibitory actions of amphetamines on hyperactivity, the feature of amphetamines believed to be important for their therapeutic action in ADHD (Gainetdinov et al., 1999; Gainetdinov and Caron, 2003). It should be noted also that the best-established agonist of TAAR1, β-PEA, shared the ability of amphetamine to induce inhibition of dopamine-dependent hyperactivity of DAT-KO mice (Gainetdinov et al., 1999; Sotnikova et al., 2004).
    Furthermore, if TAAR1 could be proven as a mediator of some of amphetamine's actions in vivo, the development of novel TAAR1-selective agonists and antagonists could provide a new approach for the treatment of amphetamine-related conditions such as addiction and/or disorders in which amphetamine is used therapeutically. In particular, because amphetamine has remained the most effective pharmacological treatment in ADHD for many years, a potential role of TAAR1 in the mechanism of the "paradoxical" effectiveness of amphetamine in this disorder should be explored.
  95. ^Berry MD (January 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases".Rev Recent Clin Trials.2(1):3–19.CiteSeerX10.1.1.329.563.doi:10.2174/157488707779318107.PMID18473983.changes in trace amines, in particular PE, have been identified as a possible factor for the onset of attention deficit/hyperactivity disorder (ADHD) [5, 27, 43, 78]. PE has been shown to induce hyperactivity and aggression, two of the cardinal clinical features of ADHD, in experimental animals [100]. Hyperactivity is also a symptom of phenylketonuria, which as discussed above is associated with a markedly elevated PE turnover [44]. Further, amphetamines, which have clinical utility in ADHD, are good ligands at trace amine receptors [2]. Of possible relevance in this aspect is modafanil, which has shown beneficial effects in ADHD patients [101] and has been reported to enhance the activity of PE at TAAR1 [102]. Conversely, methylphenidate, which is also clinically useful in ADHD, showed poor efficacy at the TAAR1 receptor [2]. In this respect it is worth noting that the enhancement of functioning at TAAR1 seen with modafanil was not a result of a direct interaction with TAAR1 [102].
    More direct evidence has been obtained recently for a role of trace amines in ADHD. Urinary PE levels have been reported to be decreased in ADHD patients in comparison to both controls and patients with autism [103-105]. Evidence for a decrease in PE levels in the brain of ADHD patients has also recently been reported [4]. In addition, decreases in the urine and plasma levels of the PE metabolite phenylacetic acid and the precursors phenylalanine and tyrosine have been reported along with decreases in plasma tyramine [103]. Following treatment with methylphenidate, patients who responded positively showed a normalization of urinary PE, whilst non-responders showed no change from baseline values [105].
  96. ^Zhukov IS, Kubarskaya LG, Tissen IY, Kozlova AA, Dagayev SG, Kashuro VA, et al. (March 2020). "Minimal Age-Related Alterations in Behavioral and Hematological Parameters in Trace Amine-Associated Receptor 1 (TAAR1) Knockout Mice".Cellular and Molecular Neurobiology.40(2):273–282.doi:10.1007/s10571-019-00721-4.PMID31399838.S2CID199511689.
  97. ^Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, et al. (February 2012)."Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia".Arthritis and Rheumatism.64(2):584–593.doi:10.1002/art.33338.PMC3237946.PMID21905019.
  98. ^abRaab S, Wang H, Uhles S, Cole N, Alvarez-Sanchez R, Künnecke B, et al. (2016)."Incretin-like effects of small molecule trace amine-associated receptor 1 agonists".Mol Metab.5(1):47–56.doi:10.1016/j.molmet.2015.09.015.PMC4703809.PMID26844206.
  99. ^Zhukov IS, Ptukha MA, Zolotoverkhaja EA, Sinitca EL, Tissen IY, Karpova IV, et al. (May 2022)."Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice".Brain Sciences.12(5): 614.doi:10.3390/brainsci12050614.PMC9139149.PMID35625001.

This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.


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