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In Vitro to in Vivo Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-11-15 , DOI: 10.1021/acsptsci.9b00062 Karen J Gregory 1 , Thomas M Bridges 2 , Rocco G Gogliotti 2 , Shaun R Stauffer 2 , Meredith J Noetzel 2 , Carrie K Jones 2 , Craig W Lindsley 2, 3, 4 , P Jeffrey Conn 2, 4, 5 , Colleen M Niswender 2, 4, 5
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-11-15 , DOI: 10.1021/acsptsci.9b00062 Karen J Gregory 1 , Thomas M Bridges 2 , Rocco G Gogliotti 2 , Shaun R Stauffer 2 , Meredith J Noetzel 2 , Carrie K Jones 2 , Craig W Lindsley 2, 3, 4 , P Jeffrey Conn 2, 4, 5 , Colleen M Niswender 2, 4, 5
Affiliation
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Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined in vitro with in vivo concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) and their relevance to in vivo concentration-response relationships. These studies identified a significant relationship between in vitro PAM cooperativity (αβ), as well as the maximal response obtained from a simple in vitro PAM concentration-response experiment, with in vivo 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 in vivo concentration of glutamate putatively relevant to the mGlu5 PAM mechanism of action. This work demonstrates the ability to merge in vitro pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations in vivo.
中文翻译：
变构调节剂浓度-作用关系的体外翻译：药物发现的含义。
GPCR的变构调节代表了药物开发中日益探索的方法。然而，由于复杂的药理作用，常常不清楚体外确定的调节剂性质与体内浓度效应现象之间的关系。我们调查了一组代谢型谷氨酸受体5（mGlu5）阳性变构调节剂（PAMs）的关键药理特性及其与体内浓度-反应关系的相关性。这些研究确定了体外PAM协同作用（αβ）以及从简单的体外PAM浓度-响应实验获得的最大响应与体内可逆转苯丙胺诱导的运动过度的显着关系。与PAM效力或亲和力不存在这种相关性。然后，将所有PAM的数据进行收敛，以计算出与mGlu5 PAM的作用机制相关的谷氨酸的体内浓度。这项工作证明了将体外药理学特征与相关行为结局融合的能力，并且还提供了一种估算体内神经递质浓度的新颖方法。
更新日期：2019-11-28
中文翻译：
变构调节剂浓度-作用关系的体外翻译：药物发现的含义。
GPCR的变构调节代表了药物开发中日益探索的方法。然而，由于复杂的药理作用，常常不清楚体外确定的调节剂性质与体内浓度效应现象之间的关系。我们调查了一组代谢型谷氨酸受体5（mGlu5）阳性变构调节剂（PAMs）的关键药理特性及其与体内浓度-反应关系的相关性。这些研究确定了体外PAM协同作用（αβ）以及从简单的体外PAM浓度-响应实验获得的最大响应与体内可逆转苯丙胺诱导的运动过度的显着关系。与PAM效力或亲和力不存在这种相关性。然后，将所有PAM的数据进行收敛，以计算出与mGlu5 PAM的作用机制相关的谷氨酸的体内浓度。这项工作证明了将体外药理学特征与相关行为结局融合的能力，并且还提供了一种估算体内神经递质浓度的新颖方法。
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