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BMS‐986122

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BMS‐986122
Identifiers
  • 2-(3-bromo-4-methoxyphenyl)-3-(4-chlorophenyl)sulfonyl-1,3-thiazolidine
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC16H15BrClNO3S2
Molar mass448.77 g·mol−1
3D model (JSmol)
  • COC1=C(C=C(C=C1)C2N(CCS2)S(=O)(=O)C3=CC=C(C=C3)Cl)Br
  • InChI=1S/C16H15BrClNO3S2/c1-22-15-7-2-11(10-14(15)17)16-19(8-9-23-16)24(20,21)13-5-3-12(18)4-6-13/h2-7,10,16H,8-9H2,1H3
  • Key:PNGJPVDGZNPZHY-UHFFFAOYSA-N

BMS‐986122 is a selective positive allosteric modulator (PAM) of the μ-opioid receptor (MOR).[1][2][3]

MOR PAMs like BMS-986122 could be useful as novel analgesics with reduced side effects compared to conventional opioid analgesics.[4][5] However, the potential specifically of BMS-986121 and BMS-986122 as pharmaceutical drugs may be restricted due to their complex synthesis.[4][3]

Mechanism of action

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BMS-986122 can enhance the affinity and efficacy of various orthosteric MOR agonists, including the endogenous opioid peptides, for the MOR.[1][2] However, its effects are dependent on the ligand, and in the case of morphine, it enhances efficacy without affecting affinity.[1] BMS‐986122 has no MOR agonist activity, is selective for the MOR, and lacks PAM activity at the δ-opioid receptor (DOR).[1] However, it has been identified as a silent allosteric modulator (SAM) of the DOR and κ-opioid receptor (KOR).[6]

Animal studies

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The drug has analgesic effects in animals.[2][4] In contrast to MOR agonists, BMS-986122 does not appear to promote opioid-induced constipation, respiratory depression, or reward.[4][7]

Discovery and development

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BMS-986122 was first described in 2013, and along with BMS-986121, was the first selective MOR PAM to be discovered.[1][8] They were identified via high-throughput screening (HTS).[1][8] Their characterization led to the discovery of a putative conserved allosteric site across the MOR and other opioid receptors.[6]

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A dual DOR and κ-opioid receptor (KOR) PAM, BMS-986187, derived from BMS-986122, has been developed and is selective for these receptors over the MOR.[9][1][2][6][10]

Another MOR PAM with a simpler synthesis, MS1, was subsequently developed and has shown similar effects to those of BMS-986122.[4][2] Additionally, ignavine, a natural MOR PAM found in Aconitum, has also been identified.[1][2][11]

In 2024, ketamine and its metabolites norketamine and hydroxynorketamine (HNK) were identified as highly potent MOR, DOR, and KOR PAMs (active at a concentration of as low as 1 nM).[12] These actions were implicated in their potential antidepressant and analgesic effects.[12]

References

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  1. ^ a b c d e f g h Livingston KE, Traynor JR (July 2018). "Allostery at opioid receptors: modulation with small molecule ligands". British Journal of Pharmacology. 175 (14): 2846–2856. doi:10.1111/bph.13823. PMC 6016636. PMID 28419415.
  2. ^ a b c d e f Hovah ME, Holzgrabe U (May 2024). "Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach". Medicinal Research Reviews. 44 (6): 2545–2599. doi:10.1002/med.22050. PMID 38751227.
  3. ^ a b Remesic M, Hruby VJ, Porreca F, Lee YS (June 2017). "Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics". ACS Chemical Neuroscience. 8 (6): 1147–1158. doi:10.1021/acschemneuro.7b00090. PMC 5689070. PMID 28368571.
  4. ^ a b c d e Pagare PP, Flammia R, Zhang Y (January 2024). "IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders". Pharmacological Research. 199: 107023. doi:10.1016/j.phrs.2023.107023. PMID 38081336.
  5. ^ Zhu L, Cui Z, Zhu Q, Zha X, Xu Y (2018). "Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects". Mini Reviews in Medicinal Chemistry. 18 (19): 1603–1610. doi:10.2174/1389557518666180716124336. PMID 30009707.
  6. ^ a b c Livingston KE, Stanczyk MA, Burford NT, Alt A, Canals M, Traynor JR (February 2018). "Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors". Molecular Pharmacology. 93 (2): 157–167. doi:10.1124/mol.117.109561. PMC 5767684. PMID 29233847.
  7. ^ Kandasamy R, Hillhouse TM, Livingston KE, Kochan KE, Meurice C, Eans SO, et al. (April 2021). "Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects". Proceedings of the National Academy of Sciences of the United States of America. 118 (16). doi:10.1073/pnas.2000017118. PMC 8072371. PMID 33846240.
  8. ^ a b Burford NT, Clark MJ, Wehrman TS, Gerritz SW, Banks M, O'Connell J, et al. (June 2013). "Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor". Proceedings of the National Academy of Sciences of the United States of America. 110 (26): 10830–10835. doi:10.1073/pnas.1300393110. PMC 3696790. PMID 23754417.
  9. ^ Wold EA, Chen J, Cunningham KA, Zhou J (January 2019). "Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts". Journal of Medicinal Chemistry. 62 (1): 88–127. doi:10.1021/acs.jmedchem.8b00875. PMC 6556150. PMID 30106578.
  10. ^ Shang Y, Yeatman HR, Provasi D, Alt A, Christopoulos A, Canals M, et al. (May 2016). "Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors". ACS Chemical Biology. 11 (5): 1220–1229. doi:10.1021/acschembio.5b00712. PMC 4950826. PMID 26841170.
  11. ^ Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, et al. (August 2016). "Ignavine: a novel allosteric modulator of the μ opioid receptor". Scientific Reports. 6: 31748. doi:10.1038/srep31748. PMC 4987652. PMID 27530869.
  12. ^ a b Gomes I, Gupta A, Margolis EB, Fricker LD, Devi LA (August 2024). "Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors". Molecular Pharmacology. 106 (5): 240–252. doi:10.1124/molpharm.124.000947. PMC 11493337. PMID 39187388.
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