Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

被引:37
作者
Livingston, Kathryn E. [1 ,2 ,5 ]
Stanczyk, M. Alexander [1 ,2 ]
Burford, Neil T. [3 ]
Alt, Andrew [3 ,6 ]
Canals, Meritxell [4 ]
Traynor, John R. [1 ,2 ]
机构
[1] Univ Michigan, Dept Pharmacol, 1150 West Med Ctr Dr,2301 MSRB III, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Edward F Domino Res Ctr, Ann Arbor, MI 48109 USA
[3] Bristol Myers Squibb Co, Res & Dev Discovery, 5 Res Pkwy, Wallingford, CT 06492 USA
[4] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia
[5] Genentech Hall, Dept Psychiat, San Francisco, CA USA
[6] Arvinas Inc, New Haven, CT USA
基金
美国国家卫生研究院;
关键词
PROTEIN-COUPLED RECEPTOR; ADENYLYL-CYCLASE; STRUCTURAL BASIS; AGONIST-BINDING; MODULATION; DISCOVERY; VALIDATION; MECHANISM; MEMBRANES; INSIGHTS;
D O I
10.1124/mol.117.109561
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the mu-opioid receptor (mu-OR). BMS-986187 is a structurally distinct PAM for the delta-opioid receptor (delta-OR) that has been reported to exhibit 100-fold selectivity in promoting mu-OR over mu-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the mu-OR and at the kappa-opioid receptor (kappa-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for delta-ORs and kappa-ORs is approximately 20- to 30-fold higher than for mu-ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (mu-OR, delta-OR, and kappa-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators.
引用
收藏
页码:157 / 167
页数:11
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