BMS-986187

BMS-986187 is a positive allosteric modulator (PAM) of the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR).^{[1][2][3][4][5][6]}

BMS-986187

Clinical data
Other names	BMS986187
Drug class	Opioid receptor positive allosteric modulator
Identifiers
IUPAC name 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9-tetrahydro-2H-xanthene-1,8-dione
CAS Number	684238-37-7
PubChem CID	17379334
IUPHAR/BPS	9748
ChemSpider	12814254
ChEMBL	ChEMBL3426789
Chemical and physical data
Formula	C31H34O4
Molar mass	470.609 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=CC=CC=C1COC2=CC=C(C=C2)C3C4=C(CC(CC4=O)(C)C)OC5=C3C(=O)CC(C5)(C)C
InChI InChI=1S/C31H34O4/c1-19-8-6-7-9-21(19)18-34-22-12-10-20(11-13-22)27-28-23(32)14-30(2,3)16-25(28)35-26-17-31(4,5)15-24(33)29(26)27/h6-13,27H,14-18H2,1-5H3 Key:UEKIYVKPQNKSDI-UHFFFAOYSA-N

The drug is highly potent as a DOR PAM, with an EC₅₀Tooltip half-maximal effective concentration of 30 nM.^[2][6] It has been found to increase the affinity of the endogenous peptide DOR agonist leu-enkephalin for the receptor by 32-fold.^[2] The drug has been found to act as a biased allosteric agonist of the DOR, activating G protein signaling (EC₅₀ = 301 nM; E_max = 92%) but with little capacity to recruit β-arrestin (EC₅₀ = 579 μM) (bias factor = 1787).^[7][8][9] Although a PAM, BMS-986187 is able to activate the DOR even in the absence of an orthosteric agonist, and as such, has been referred to as an "ago-PAM".^[2]

Subsequent to its discovery, BMS-987187 was found to act as a potent KOR PAM as well.^[1][4] It is also a weak μ-opioid receptor (MOR) PAM (EC₅₀ = 3,000 nM), but has 100-fold selectivity for potentiation of the DOR over the MOR.^[2][4][6] BMS-986187 has about 20- to 30-fold higher affinity for the conserved allosteric site on the DOR and KOR relative to the corresponding site on the MOR.^[1][4] It is not a PAM of the nociceptin receptor, which is less homologous to the other opioid receptors.^[4]

The drug was first described by 2015 and was the first selective DOR PAM as well as the first selective KOR PAM to be discovered.^[3][4][6] It was identified via high-throughput screening (HTS).^[2] DOR PAMs like BMS-986187 might prove to be useful in the clinical treatment of certain gastrointestinal disorders.^[10][11]

See also

• BMS‐986122