Chemistry:BMS‐986122

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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]

Pharmacology

Pharmacodynamics

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]

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] The drug has been found to attenuate opioid tolerance in rodents, specifically in terms of analgesia.[8] Besides its analgesic effects, BMS-986122 has been found to enhance the analgesic effects of non-opioid analgesics such as clonidine and gabapentin in rodents.[9]

History

BMS-986122 was first described in 2013, and along with BMS-986121, was the first selective MOR PAM to be discovered.[1][10] They were identified via high-throughput screening (HTS).[1][10] Their characterization led to the discovery of a putative conserved allosteric site across the MOR and other opioid receptors.[6]

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.[11][1][2][6][12]

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][13]

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).[14] These actions were implicated in their potential antidepressant and analgesic effects.[14]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Allostery at opioid receptors: modulation with small molecule ligands". British Journal of Pharmacology 175 (14): 2846–2856. July 2018. doi:10.1111/bph.13823. PMID 28419415. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach". Medicinal Research Reviews 44 (6): 2545–2599. May 2024. doi:10.1002/med.22050. PMID 38751227. 
  3. ↑ 3.0 3.1 "Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics". ACS Chemical Neuroscience 8 (6): 1147–1158. June 2017. doi:10.1021/acschemneuro.7b00090. PMID 28368571. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders". Pharmacological Research 199. January 2024. doi:10.1016/j.phrs.2023.107023. PMID 38081336. 
  5. ↑ "Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects". Mini Reviews in Medicinal Chemistry 18 (19): 1603–1610. 2018. doi:10.2174/1389557518666180716124336. PMID 30009707. 
  6. ↑ 6.0 6.1 6.2 "Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors". Molecular Pharmacology 93 (2): 157–167. February 2018. doi:10.1124/mol.117.109561. PMID 29233847. 
  7. ↑ "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. doi:10.1073/pnas.2000017118. PMID 33846240. Bibcode: 2021PNAS..11800017K. 
  8. ↑ "The Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 Attenuates Opioid Tolerance (Abstract ID: 225965)". The Journal of Pharmacology and Experimental Therapeutics 393 (5). 2026. doi:10.1016/j.jpet.2026.104279. 
  9. ↑ "Enhancement of the Antinociceptive Effects of Non-Opioid Analgesics by the Opioid Receptor Modulator BMS-986122 (Abstract ID: 230565)". The Journal of Pharmacology and Experimental Therapeutics 393 (5). 2026. doi:10.1016/j.jpet.2026.104033. 
  10. ↑ 10.0 10.1 "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. doi:10.1073/pnas.1300393110. PMID 23754417. Bibcode: 2013PNAS..11010830B. 
  11. ↑ "Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts". Journal of Medicinal Chemistry 62 (1): 88–127. January 2019. doi:10.1021/acs.jmedchem.8b00875. PMID 30106578. 
  12. ↑ "Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors". ACS Chemical Biology 11 (5): 1220–1229. May 2016. doi:10.1021/acschembio.5b00712. PMID 26841170. 
  13. ↑ "Ignavine: a novel allosteric modulator of the μ opioid receptor". Scientific Reports 6. August 2016. doi:10.1038/srep31748. PMID 27530869. Bibcode: 2016NatSR...631748O. 
  14. ↑ 14.0 14.1 "Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors". Molecular Pharmacology 106 (5): 240–252. August 2024. doi:10.1124/molpharm.124.000947. PMID 39187388. 



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