Gregory Karen J, Bridges Thomas M, Gogliotti Rocco G, Stauffer Shaun R, Noetzel Meredith J, Jones Carrie K, Lindsley Craig W, Conn P Jeffrey, Niswender Colleen M
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia.
Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
ACS Pharmacol Transl Sci. 2019 Nov 15;2(6):442-452. doi: 10.1021/acsptsci.9b00062. eCollection 2019 Dec 13.
Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined with concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu) positive allosteric modulators (PAMs) and their relevance to concentration-response relationships. These studies identified a significant relationship between PAM cooperativity (αβ), as well as the maximal response obtained from a simple PAM concentration-response experiment, with efficacy for reversal of amphetamine-induced hyperlocomotion. This correlation did not exist with PAM potency or affinity. Data across PAMs were then converged to calculate an concentration of glutamate putatively relevant to the mGlu PAM mechanism of action. This work demonstrates the ability to merge pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations .
G蛋白偶联受体（GPCRs）的变构调节在药物研发中已成为一种探索日益深入的方法。然而，由于药理学机制复杂，通过浓度效应现象确定的调节剂性质之间的关系往往并不明确。我们研究了一组代谢型谷氨酸受体5（mGlu）正向变构调节剂（PAMs）的关键药理学性质及其与浓度-反应关系的相关性。这些研究确定了PAM协同性（αβ）以及从简单的PAM浓度-反应实验中获得的最大反应与苯丙胺诱导的运动亢进逆转效力之间存在显著关系。这种相关性在PAM效力或亲和力方面并不存在。然后整合不同PAMs的数据，计算出可能与mGlu PAM作用机制相关的谷氨酸浓度。这项工作证明了将药理学特征与相关行为结果相结合的能力，同时也提供了一种估计神经递质浓度的新方法。
