Iso Yasuyoshi, Grajkowska Ewa, Wroblewski Jarda T, Davis Jared, Goeders Nicholas E, Johnson Kenneth M, Sanker Subramaniam, Roth Bryan L, Tueckmantel Werner, Kozikowski Alan P
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
J Med Chem. 2006 Feb 9;49(3):1080-100. doi: 10.1021/jm050570f.
Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.
最近的遗传学和药理学研究表明，代谢型谷氨酸受体5亚型（mGluR5）可能是一个可成药靶点，有望用于开发治疗包括药物滥用在内的各种中枢神经系统疾病的新疗法。特别是，mGluR5领域的大量研究都致力于寻找与主要激动剂谷氨酸结合位点不同的、能与变构调节位点结合的配体。2-甲基-6-（苯乙炔基）吡啶（MPEP）及其类似物3-[(2-甲基-4-噻唑基)乙炔基]吡啶（MTEP）已被证明是mGluR5的选择性强效非竞争性拮抗剂。鉴于本研究结果表明MTEP可防止因呈现先前与可卡因可得性相关的环境线索而导致的可卡因自我给药恢复，我们制备了一系列MTEP类似物，旨在更好地了解与其拮抗剂效力相关的结构特征，并最终研究此类化合物对抑制可卡因自我给药的作用。这些努力已导致鉴定出比MPEP或MTEP作为mGluR5拮抗剂效力更高的化合物。两种化合物19和59表现出作为mGluR5拮抗剂的功能活性分别比MTEP高490倍和230倍。
