In vitro metabolic studies on the selective metabotropic glutamate receptor sub-type 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP)
In vitro metabolic studies on the selective metabotropic glutamate receptor sub-type 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP)
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DOI：
10.1016/j.neulet.2005.08.032
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发表时间：
2006-01-02
影响因子：
2.5
通讯作者：
King, CD
中科院分区：
文献类型：
--
作者：
Green, MD;Yang, XQ;King, CD
代谢型谷氨酸受体（mGluR）是G蛋白偶联受体，其在CNS中的调节途径中起主要作用，并且已被认为在疼痛、精神障碍和其他神经系统状态中具有药理学意义。3-[（2-甲基-1，3-噻唑-4-基）乙炔基]-吡啶（MTEP）是mGluR亚型5的特异性和选择性拮抗剂。先前使用大鼠肝微粒体的研究表明，MTEP的主要氧化代谢产物是羟甲基代谢产物（M1）、两种氧化物（M2和M4）、噻唑开环代谢产物（M3）和CO2（M5）。在本研究中，我们研究了MTEP在肝微粒体中的代谢，并表达了大鼠和人的MTEP亚型。在大鼠肝微粒体中。代谢稳定性研究准确地预测了MTEP的体内清除。将MTEP与表达的大鼠和人CYP同工型一起孵育显示，CYP 1A和CYP 2C同工型主要负责该化合物的代谢。结果表明，MTEP代谢的种属差异是可能的，并可能导致该化合物生物学效应的种属差异。(C)2005爱思唯尔爱尔兰有限公司保留所有权利。
Metabotropic glutamate receptors (mGluR) are G-protein-coupled receptors that play a major rote in modulatory pathways in the CNS and have been suggested to have pharmacological implications in pain, psychiatric disorders and other neurological states. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) is a specific and selective antagonist for the mGluR sub-type 5. Previous studies using rat liver microsomes showed that the major oxidative metabolites of MTEP are a hydroxymethyl metabolite (M1), two oxides (M2 and M4), a thiazole-ring opened metabolite (M3) and CO2 (M5). In the present study, we examined the metabolism of MTEP in liver microsomes and expressed rat and human CYP isoforms. In rat liver microsomes. metabolic stability studies accurately predicted the in vivo clearance for MTEP Incubation of MTEP with expressed rat and human CYP isoforms showed that CYP1A and CYP2C isoforms are primarily responsible for the metabolism of this compound. The results suggest that species differences in MTEP metabolism is possible and could contribute to specie-differences in biological effects of the compound. (C) 2005 Elsevier Ireland Ltd. All rights reserved.