1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.
1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.
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DOI：
10.1073/pnas.83.22.8784
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发表时间：
1986-11
影响因子：
11.1
通讯作者：
E. Weber;M. Sonders;M. Quarum;S. Mclean;S. Pou;J. Keana
中科院分区：
文献类型：
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作者：
E. Weber;M. Sonders;M. Quarum;S. Mclean;S. Pou;J. Keana
大脑Sigma型受体被认为介导了某些苯并吗啡阿片类药物对人类的致幻作用。由于缺乏有效和选择性的配体，Sigma受体的生化特性一直很困难。本文报道了1，3-二(2-[5-~3H]甲苯基)胍([~3H]Tol2Gdn)的合成和表征，它与豚鼠脑膜制剂中的一组结合位点具有高亲和力。[~3H]Tol2Gn结合部位对已知具有Sigma行为效应的苯并吗阿片类右旋光学异构体具有立体选择性。此外，[~3H]Tol2Gdn结合位点对氟哌啶醇和吩噻嗪类抗精神病药物有很高的亲和力，这两种药物在人类中具有抗幻觉特性。[~3H]Tol2Gn结合的药物选择性与氚(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine[+]-[~3H]3-PPP与豚鼠脑膜受体结合的药物选择性密切相关。(+)-[~3H]-3-PPP被认为是一种选择性的Sigma受体配体[Largent，B.L.，Gundlach，A.L.&Snyder，S.H.(1984)Proc.娜塔莉。阿卡德。SCI。美国82,4983-4987]。在载玻片的大鼠和豚鼠的脑切片上，用[~3H]Tol2Gdon进行受体放射自显影，发现在大脑的边缘和感觉运动结构中有丰富的结合的异质分布模式。这些结果表明，[~3H]Tol2Gn是Sigma位点的选择性配体。Sigma受体探针的问世将极大地促进脑中Sigma受体的生理、生化和药理学特征的研究。
Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-[5-3H]tolyl)guanidine ([3H]Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The [3H]Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the [3H]Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of [3H]Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)-[3H]3-PPP) binding to guinea pig brain membrane receptors. (+)-[3H]3-PPP has been proposed to be a selective sigma-receptor ligand [Largent, B. L., Gundlach, A. L. & Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987]. Receptor autoradiography using [3H]Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that [3H]Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.