Wikipedia

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 namesBMS986187
Drug classOpioid receptor positive allosteric modulator
Identifiers
  • 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9-tetrahydro-2H-xanthene-1,8-dione
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
Chemical and physical data
FormulaC31H34O4
Molar mass470.609 g·mol−1
3D model (JSmol)
  • CC1=CC=CC=C1COC2=CC=C(C=C2)C3C4=C(CC(CC4=O)(C)C)OC5=C3C(=O)CC(C5)(C)C
  • 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; Emax = 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

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References

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  1. ^ a b c Wold EA, Chen J, Cunningham KA, Zhou J (January 2019). "Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts". Journal of Medicinal Chemistry. 62 (1): 88–127. doi:10.1021/acs.jmedchem.8b00875. PMC 6556150. PMID 30106578. BMS-986187 (179), with a chemically novel core compared to previous BMS series, was discovered as an effective PAM at the DOR and at the κ-opioid receptor (KOR) rather than the MOR with an approximately 20-to 30-fold higher affinity in the allosteric ternary complex model.261
  2. ^ a b c d e f Livingston KE, Traynor JR (July 2018). "Allostery at opioid receptors: modulation with small molecule ligands". British Journal of Pharmacology. 175 (14): 2846–2856. doi:10.1111/bph.13823. PMC 6016636. PMID 28419415.
  3. ^ a b Hovah ME, Holzgrabe U (May 2024). "Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach". Medicinal Research Reviews. doi:10.1002/med.22050. PMID 38751227.
  4. ^ a b c d e f Livingston KE, Stanczyk MA, Burford NT, Alt A, Canals M, Traynor JR (February 2018). "Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors". Molecular Pharmacology. 93 (2): 157–167. doi:10.1124/mol.117.109561. PMC 5767684. PMID 29233847.
  5. ^ Shang Y, Yeatman HR, Provasi D, Alt A, Christopoulos A, Canals M, Filizola M (May 2016). "Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors". ACS Chemical Biology. 11 (5): 1220–1229. doi:10.1021/acschembio.5b00712. PMC 4950826. PMID 26841170.
  6. ^ a b c d Burford NT, Livingston KE, Canals M, Ryan MR, Budenholzer LM, Han Y, Shang Y, Herbst JJ, O'Connell J, Banks M, Zhang L, Filizola M, Bassoni DL, Wehrman TS, Christopoulos A, Traynor JR, Gerritz SW, Alt A (May 2015). "Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor". J Med Chem. 58 (10): 4220–4229. doi:10.1021/acs.jmedchem.5b00007. PMC 4703104. PMID 25901762.
  7. ^ Turnaturi R, Chiechio S, Salerno L, Rescifina A, Pittalà V, Cantarella G, Tomarchio E, Parenti C, Pasquinucci L (December 2019). "Progress in the development of more effective and safer analgesics for pain management". Eur J Med Chem. 183: 111701. doi:10.1016/j.ejmech.2019.111701. PMID 31550662.
  8. ^ Varga BR, Streicher JM, Majumdar S (April 2023). "Strategies towards safer opioid analgesics-A review of old and upcoming targets". Br J Pharmacol. 180 (7): 975–993. doi:10.1111/bph.15760. PMC 9133275. PMID 34826881.
  9. ^ Stanczyk MA, Livingston KE, Chang L, Weinberg ZY, Puthenveedu MA, Traynor JR (June 2019). "The δ-opioid receptor positive allosteric modulator BMS 986187 is a G-protein-biased allosteric agonist". Br J Pharmacol. 176 (11): 1649–1663. doi:10.1111/bph.14602. PMC 6514288. PMID 30710458.
  10. ^ Saito A, Alvi S, Valant C, Christopoulos A, Carbone SE, Poole DP (July 2024). "Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders". Br J Pharmacol. 181 (14): 2232–2246. doi:10.1111/bph.16023. PMID 36565295.
  11. ^ DiCello JJ, Carbone SE, Saito A, Pham V, Szymaszkiewicz A, Gondin AB, Alvi S, Marique K, Shenoy P, Veldhuis NA, Fichna J, Canals M, Christopoulos A, Valant C, Poole DP (January 2022). "Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders". Am J Physiol Gastrointest Liver Physiol. 322 (1): G66–G78. doi:10.1152/ajpgi.00297.2021. PMID 34755545.
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