BMS‐986122 explained

Width:175px
Cas Number:313669-88-4
Pubchem:4644453
Chemspiderid:3834202
Iupac Name:2-(3-bromo-4-methoxyphenyl)-3-(4-chlorophenyl)sulfonyl-1,3-thiazolidine
C:16
H:15
Br:1
Cl:1
N:1
O:3
S:2
Smiles:COC1=C(C=C(C=C1)C2N(CCS2)S(=O)(=O)C3=CC=C(C=C3)Cl)Br
Stdinchi: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
Stdinchikey:PNGJPVDGZNPZHY-UHFFFAOYSA-N

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

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

Mechanism of action

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

Animal studies

The drug has analgesic effects in animals.[5] In contrast to MOR agonists, BMS-986122 does not appear to promote opioid-induced constipation, respiratory depression, or reward.[6]

Discovery and development

BMS-986122 was first described in 2013, and along with BMS-986121, was the first selective MOR PAM to be discovered.[7] They were identified via high-throughput screening (HTS). Their characterization led to the discovery of a putative conserved allosteric site across the MOR and other opioid receptors.[8]

Related compounds

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] [10]

Another MOR PAM with a simpler synthesis, MS1, was subsequently developed and has shown similar effects to those of BMS-986122. Additionally, ignavine, a natural MOR PAM found in Aconitum, has also been identified.[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 1nM). These actions were implicated in their potential antidepressant and analgesic effects.[12]

Notes and References

  1. Livingston KE, Traynor JR . Allostery at opioid receptors: modulation with small molecule ligands . British Journal of Pharmacology . 175 . 14 . 2846–2856 . July 2018 . 28419415 . 6016636 . 10.1111/bph.13823 .
  2. Hovah ME, Holzgrabe U . Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach . Medicinal Research Reviews . 44. 6. May 2024 . 2545–2599 . 38751227 . 10.1002/med.22050 .
  3. Zhu L, Cui Z, Zhu Q, Zha X, Xu Y . Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects . Mini Reviews in Medicinal Chemistry . 18 . 19 . 1603–1610 . 2018 . 30009707 . 10.2174/1389557518666180716124336 .
  4. Remesic M, Hruby VJ, Porreca F, Lee YS . Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics . ACS Chemical Neuroscience . 8 . 6 . 1147–1158 . June 2017 . 28368571 . 5689070 . 10.1021/acschemneuro.7b00090 .
  5. Pagare PP, Flammia R, Zhang Y . IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders . Pharmacological Research . 199 . 107023 . January 2024 . 38081336 . 10.1016/j.phrs.2023.107023 . free .
  6. Kandasamy R, Hillhouse TM, Livingston KE, Kochan KE, Meurice C, Eans SO, Li MH, White AD, Roques BP, McLaughlin JP, Ingram SL, Burford NT, Alt A, Traynor JR . 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 . April 2021 . 33846240 . 8072371 . 10.1073/pnas.2000017118 . free .
  7. Burford NT, Clark MJ, Wehrman TS, Gerritz SW, Banks M, O'Connell J, Traynor JR, Alt A . 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 . June 2013 . 23754417 . 3696790 . 10.1073/pnas.1300393110 . free .
  8. Livingston KE, Stanczyk MA, Burford NT, Alt A, Canals M, Traynor JR . Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors . Molecular Pharmacology . 93 . 2 . 157–167 . February 2018 . 29233847 . 5767684 . 10.1124/mol.117.109561 .
  9. Wold EA, Chen J, Cunningham KA, Zhou J . Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts . Journal of Medicinal Chemistry . 62 . 1 . 88–127 . January 2019 . 30106578 . 6556150 . 10.1021/acs.jmedchem.8b00875 .
  10. Shang Y, Yeatman HR, Provasi D, Alt A, Christopoulos A, Canals M, Filizola M . Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors . ACS Chemical Biology . 11 . 5 . 1220–1229 . May 2016 . 26841170 . 4950826 . 10.1021/acschembio.5b00712 .
  11. Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, Yamamoto M, Warabi E, Sudo Y, Yokoyama A, Miyano K, Hirokawa T, Uezono Y . Ignavine: a novel allosteric modulator of the μ opioid receptor . Scientific Reports . 6 . 31748 . August 2016 . 27530869 . 4987652 . 10.1038/srep31748 .
  12. Gomes I, Gupta A, Margolis EB, Fricker LD, Devi LA . Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors . Molecular Pharmacology . 106. 5. August 2024 . 240–252 . 39187388 . 10.1124/molpharm.124.000947 . 11493337 . November 1, 2025 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "BMS‐986122".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2025, A B Cryer, All Rights Reserved. Cookie policy.