BMS‐986122

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

BMS‐986122

Identifiers
IUPAC name 2-(3-bromo-4-methoxyphenyl)-3-(4-chlorophenyl)sulfonyl-1,3-thiazolidine
CAS Number	313669-88-4
PubChem CID	4644453
ChemSpider	3834202
Chemical and physical data
Formula	C16H15BrClNO3S2
Molar mass	448.77 g·mol−1
3D model (JSmol)	Interactive image
SMILES COC1=C(C=C(C=C1)C2N(CCS2)S(=O)(=O)C3=CC=C(C=C3)Cl)Br
InChI 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

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]