BMS‐986122
Chemical compound
From Wikipedia, the free encyclopedia
BMS‐986122 is a selective positive allosteric modulator (PAM) of the μ-opioid receptor (MOR).[1][2][3]
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| Formula | C16H15BrClNO3S2 |
| Molar mass | 448.77 g·mol−1 |
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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
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
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
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]
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][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]