Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery (D.E.O., D.M.S., H.P.C., A.S.F., C.W.L, C.M.N., P.J.C.), Vanderbilt Brain Institute (P.J.C.), and Vanderbilt Kennedy Center (C.M.N., P.J.C.), Vanderbilt University, Nashville, Tennessee; AstraZeneca Neuroscience Innovative Medicines, AstraZeneca, Cambridge, Massachusetts (A.J.C., S.S.W.); and AstraZeneca Pharmaceutical Sciences, AstraZeneca, Mölndal, Sweden (J.B., C.S.E.).
Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery (D.E.O., D.M.S., H.P.C., A.S.F., C.W.L, C.M.N., P.J.C.), Vanderbilt Brain Institute (P.J.C.), and Vanderbilt Kennedy Center (C.M.N., P.J.C.), Vanderbilt University, Nashville, Tennessee; AstraZeneca Neuroscience Innovative Medicines, AstraZeneca, Cambridge, Massachusetts (A.J.C., S.S.W.); and AstraZeneca Pharmaceutical Sciences, AstraZeneca, Mölndal, Sweden (J.B., C.S.E.)
Mol Pharmacol. 2018 May;93(5):526-540. doi: 10.1124/mol.117.110114. Epub 2018 Mar 15.
Allosteric modulation of metabotropic glutamate receptor 2 (mGlu) has demonstrated efficacy in preclinical rodent models of several brain disorders, leading to industry and academic drug discovery efforts. Although the pharmacology and binding sites of some mGlu allosteric modulators have been characterized previously, questions remain about the nature of the allosteric mechanism of cooperativity with glutamate and whether structurally diverse allosteric modulators bind in an identical manner to specific allosteric sites. To further investigate the in vitro pharmacology of mGlu allosteric modulators, we developed and characterized a novel mGlu positive allosteric modulator (PAM) radioligand in parallel with functional studies of a structurally diverse set of mGlu PAMs and negative allosteric modulators (NAMs). Using an operational model of allosterism to analyze the functional data, we found that PAMs affect both the affinity and efficacy of glutamate at mGlu, whereas NAMs predominantly affect the efficacy of glutamate in our assay system. More importantly, we found that binding of a novel mGlu PAM radioligand was inhibited by multiple structurally diverse PAMs and NAMs, indicating that they may bind to the mGlu allosteric site labeled with the novel mGlu PAM radioligand; however, further studies suggested that these allosteric modulators do not all interact with the radioligand in an identical manner. Together, these findings provide new insights into the binding sites and modes of efficacy of different structurally and functionally distinct mGlu allosteric modulators and suggest that different ligands either interact with distinct sites or adapt different binding poses to shared allosteric site(s).
变构调节代谢型谷氨酸受体 2（mGlu）在几种脑疾病的临床前啮齿动物模型中显示出疗效，导致行业和学术药物发现的努力。虽然一些 mGlu 变构调节剂的药理学和结合位点已经被先前表征，但是关于变构协同作用与谷氨酸的性质以及结构多样的变构调节剂是否以相同的方式结合到特定的变构位点的问题仍然存在。为了进一步研究 mGlu 变构调节剂的体外药理学，我们开发并表征了一种新型的 mGlu 正变构调节剂（PAM）放射性配体，同时对一组结构多样的 mGlu PAMs 和负变构调节剂（NAMs）进行了功能研究。使用变构作用的操作模型来分析功能数据，我们发现 PAMs 影响 mGlu 上谷氨酸的亲和力和效力，而 NAMs 主要影响我们测定系统中谷氨酸的效力。更重要的是，我们发现一种新型的 mGlu PAM 放射性配体的结合受到多种结构多样的 PAMs 和 NAMs 的抑制，表明它们可能与新型 mGlu PAM 放射性配体标记的 mGlu 变构位点结合;然而，进一步的研究表明，这些变构调节剂并非都以相同的方式与放射性配体相互作用。总之，这些发现为不同结构和功能上不同的 mGlu 变构调节剂的结合位点和效力模式提供了新的见解，并表明不同的配体要么与不同的位点相互作用，要么适应不同的结合构象以共享变构位点。
