Chemistry: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]
The drug is highly potent as a DOR PAM, with an EC50 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
References
- ↑ 1.0 1.1 1.2 "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. "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".
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "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.
- ↑ 3.0 3.1 "Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach". Medicinal Research Reviews. May 2024. doi:10.1002/med.22050. PMID 38751227.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "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.
- ↑ "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.
- ↑ 6.0 6.1 6.2 6.3 "Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor". J Med Chem 58 (10): 4220–4229. May 2015. doi:10.1021/acs.jmedchem.5b00007. PMID 25901762.
- ↑ "Progress in the development of more effective and safer analgesics for pain management". Eur J Med Chem 183. December 2019. doi:10.1016/j.ejmech.2019.111701. PMID 31550662.
- ↑ "Strategies towards safer opioid analgesics-A review of old and upcoming targets". Br J Pharmacol 180 (7): 975–993. April 2023. doi:10.1111/bph.15760. PMID 34826881.
- ↑ "The δ-opioid receptor positive allosteric modulator BMS 986187 is a G-protein-biased allosteric agonist". Br J Pharmacol 176 (11): 1649–1663. June 2019. doi:10.1111/bph.14602. PMID 30710458.
- ↑ "Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders". Br J Pharmacol 181 (14): 2232–2246. July 2024. doi:10.1111/bph.16023. PMID 36565295.
- ↑ "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. January 2022. doi:10.1152/ajpgi.00297.2021. PMID 34755545. https://nottingham-repository.worktribe.com/output/6738511.
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