IBNtxA

IBNtxA
Clinical data
ATC code	none;
Identifiers
	IUPAC name N-[(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-yl]-3-iodobenzamide;
PubChemCID	51003467;
ChemSpider	26617995;
ChEMBL	ChEMBL1795711;
CompTox Dashboard(EPA)	DTXSID201018246;
Chemical and physical data
Formula	C27H29IN2O4
Molar mass	572.443g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1C[C@]2([C@H]3CC4=C5[C@@]2(CCN3CC6CC6)[C@H]([C@@H]1NC(=O)C7=CC(=CC=C7)I)OC5=C(C=C4)O)O;
	InChI InChI=1S/C27H29IN2O4/c28-18-3-1-2-17(12-18)25(32)29-19-8-9-27(33)21-13-16-6-7-20(31)23-22(16)26(27,24(19)34-23)10-11-30(21)14-15-4-5-15/h1-3,6-7,12,15,19,21,24,31,33H,4-5,8-11,13-14H2,(H,29,32)/t19-,21-,24+,26+,27-/m1/s1; Key:FGAFDGWRFOJPRY-XGTKUTNFSA-N;

IBNtxA,or3-iodobenzoyl naltrexamine,is an atypicalopioid analgesicdrug derived fromnaltrexone.In animal studies it produces potent analgesic effects that are blocked bylevallorphan^[1]and so appear to beμ-opioidmediated, but it fails to produceconstipationorrespiratory depression,and is neither rewarding or aversive^[2]inconditioned place preferenceprotocols.^[3]These unusual properties are thought to result from agonist action at asplice variantorheterodimerof the μ-opioid receptor,^[4]rather than at the classical full length form targeted by conventional opioid drugs.^[5]

In the Radioligand binding assay it has shown to have affinities of 0.11nM at the MOR, 0.24nM at the DOR and 0.03nM at the KOR and in the Hot- Plate Assay it is shown to be around 20x more potent thanmorphine.Azido Aryl Analogues of IBNtxA retain significant activity at the MOR.^[6]

References

^Majumdar S, Subrath J, Le Rouzic V, Polikar L, Burgman M, Nagakura K, Ocampo J, Haselton N, Pasternak AR, Grinnell S, Pan YX, Pasternak GW (2012)."Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants".J. Med. Chem.55(14): 6352–62.doi:10.1021/jm300305c.PMC3412067.PMID 22734622.
^Majumdar S, Grinnell S, Le Rouzic V, et al. (December 2011)."Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects".Proc. Natl. Acad. Sci. U.S.A.108(49): 19778–83.Bibcode:2011PNAS..10819778M.doi:10.1073/pnas.1115231108.PMC3241767.PMID 22106286.
^Grinnell SG, Majumdar S, Narayan A, Le Rouzic V, Ansonoff M, Pintar JE, Pasternak GW (2014)."Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA".J. Pharmacol. Exp. Ther.350(3): 710–8.doi:10.1124/jpet.114.213199.PMC4152881.PMID 24970924.
^Wieskopf JS, Pan YX, Marcovitz J, Tuttle AH, Majumdar S, Pidakala J, Pasternak GW, Mogil JS (2014)."Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene".Pain.155(10): 2063–70.doi:10.1016/j.pain.2014.07.014.PMC4372857.PMID 25093831.
^Keck TM, Uddin MM, Babenko E, Wu C, Moura-Letts G. Abuse Liability and Anti-Addiction Potential of the Atypical Mu Opioid Receptor Agonist IBNtxA.The FASEB Journal31 (1 Supplement), 985.4-985.4, 2017
^Grinnell SG, Rajendra U (2021)."Synthesis and Characterization of Azido Aryl Analogs of IBNtxA for Radio-Photoaffinity Labeling Opioid Receptors in Cell Lines and in Mouse Brain".Cell Mol Neurobiology.5(41): 977–993.doi:10.1007/s10571-020-00867-6.PMC7671950.PMID 32424771.

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[pmid22734622-1] Majumdar S, Subrath J, Le Rouzic V, Polikar L, Burgman M, Nagakura K, Ocampo J, Haselton N, Pasternak AR, Grinnell S, Pan YX, Pasternak GW (2012)."Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants".J. Med. Chem.55(14): 6352–62.doi:10.1021/jm300305c.PMC3412067.PMID 22734622.

[2] Majumdar S, Grinnell S, Le Rouzic V, et al. (December 2011)."Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects".Proc. Natl. Acad. Sci. U.S.A.108(49): 19778–83.Bibcode:2011PNAS..10819778M.doi:10.1073/pnas.1115231108.PMC3241767.PMID 22106286.

[pmid24970924-3] Grinnell SG, Majumdar S, Narayan A, Le Rouzic V, Ansonoff M, Pintar JE, Pasternak GW (2014)."Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA".J. Pharmacol. Exp. Ther.350(3): 710–8.doi:10.1124/jpet.114.213199.PMC4152881.PMID 24970924.

[pmid25093831-4] Wieskopf JS, Pan YX, Marcovitz J, Tuttle AH, Majumdar S, Pidakala J, Pasternak GW, Mogil JS (2014)."Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene".Pain.155(10): 2063–70.doi:10.1016/j.pain.2014.07.014.PMC4372857.PMID 25093831.

[5] Keck TM, Uddin MM, Babenko E, Wu C, Moura-Letts G. Abuse Liability and Anti-Addiction Potential of the Atypical Mu Opioid Receptor Agonist IBNtxA.The FASEB Journal31 (1 Supplement), 985.4-985.4, 2017

[6] Grinnell SG, Rajendra U (2021)."Synthesis and Characterization of Azido Aryl Analogs of IBNtxA for Radio-Photoaffinity Labeling Opioid Receptors in Cell Lines and in Mouse Brain".Cell Mol Neurobiology.5(41): 977–993.doi:10.1007/s10571-020-00867-6.PMC7671950.PMID 32424771.

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