Agonist-antagonist
In pharmacology the termagonist-antagonistormixed agonist/antagonistis used to refer to a drug which under some conditions behaves as anagonist(a substance that fully activates the receptor that it binds to) while under other conditions, behaves as anantagonist(a substance that binds to a receptor but does not activate and can block the activity of other agonists).
Types of mixed agonist/antagonist includereceptor ligandsthat act as agonist for some receptor types and antagonist for others[1]or agonist in some tissues while antagonist in others (also known asselective receptor modulators).
Synaptic receptors
[edit]For synaptic receptors, an agonist is a compound that increases the activation of the receptor by binding directly to it or by increasing the amount of timeneurotransmittersare in the synaptic cleft. An antagonist is a compound that has the opposite effect of an agonist. It decreases the activation of a synaptic receptor by binding and blocking neurotransmitters from binding or by decreasing the amount of time neurotransmitters are in the synaptic cleft. These actions can be achieved via multiple mechanisms. A common mechanism for agonists isreuptake inhibition,where the agonist blocks neurotransmitters from reentering the pre-synaptic axon terminal. This gives the neurotransmitter more time in the synaptic cleft to act on the synaptic receptors. Conversely, antagonists often bind directly to receptors in the synaptic cleft, effectively blocking neurotransmitters from binding.
At theAlpha adrenoceptors,(R)-3-nitrobiphenylineis an α2Cselective agonist as well as being a weakantagonistat the α2Aand α2Bsubtypes.[2][3]
Agonist-antagonist opioids
[edit]The best known agonist-antagonists areopioids.Examples of such opioids are:
- pentazocine,agonist at thekappa(κ) andsigma(σ) and has a weak antagonist action at themu opioid receptor(μ)[4]
- butorphanol,partial agonist at μ- and a pure agonist at κ-opioid receptor and antagonist activity at thedelta opioid receptor(δ)[5]
- nalbuphine,κ-agonist/μ-antagonist analgesic[6]
Agonist–antagonist opioids usually have aceiling effect– over particular dose they don't increase their potency.[7]Hence agonist–antagonist opioids have a lower addiction potential but also lower analgesic efficacy and are more likely to producepsychotomimeticeffects.[8]
Agonist–antagonist opioids that blockdeltawhile activatingmu opioid receptorsproduce analgesia without the development oftolerance.[9]
See also
[edit]References
[edit]- ^Hoskin PJ, Hanks GW (March 1991). "Opioid agonist-antagonist drugs in acute and chronic pain states".Drugs.41(3): 326–44.doi:10.2165/00003495-199141030-00002.PMID1711441.S2CID27694903.
- ^Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, et al. (August 2007). "Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and Alpha 2C-subtype selective agonist".Journal of Medicinal Chemistry.50(16): 3964–8.doi:10.1021/jm061487a.PMID17630725.
- ^Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, et al. (November 2010). "Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence".Journal of Medicinal Chemistry.53(21): 7825–35.doi:10.1021/jm100977d.PMID20925410.
- ^Hollister LE (17 July 1991). "AMA Drug Evaluations Annual 1991".JAMA: The Journal of the American Medical Association.266(3): 97.doi:10.1001/jama.1991.03470030126039.
- ^Commiskey S, Fan LW, Ho IK, Rockhold RW (June 2005)."Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors".Journal of Pharmacological Sciences.98(2): 109–16.doi:10.1254/jphs.CRJ05001X.PMID15942128.
- ^Schmidt WK, Tam SW, Shotzberger GS, Smith DH, Clark R, Vernier VG (February 1985). "Nalbuphine".Drug and Alcohol Dependence.14(3–4): 339–62.doi:10.1016/0376-8716(85)90066-3.PMID2986929.
- ^Benson GJ, Tranquilli WJ (March 1992). "Advantages and guidelines for using opioid agonist-antagonist analgesics".The Veterinary Clinics of North America. Small Animal Practice.22(2): 363–5.doi:10.1016/S0195-5616(92)50637-4.PMID1585578.
- ^Lasagna L (December 1987)."Benefit-risk ratio of agonist-antagonist analgesics".Drug and Alcohol Dependence.20(4): 385–93.doi:10.1111/j.1360-0443.1989.tb00595.x.PMID2894291.
- ^Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG (July 2009)."Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile".British Journal of Anaesthesia.103(1): 38–49.doi:10.1093/bja/aep129.PMID19474215.