Sonesson C, Lin C H, Hansson L, Waters N, Svensson K, Carlsson A, Smith M W, Wikström H
Department of Pharmacology, University of Göteborg, Sweden.
J Med Chem. 1994 Aug 19;37(17):2735-53. doi: 10.1021/jm00043a013.
A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.
已制备了一系列（S）-苯基哌啶，其中芳环和氮上的取代基有所变化。对它们进行了药理学评估，以探究这些取代基与中枢多巴胺（DA）受体相互作用的重要性。根据大鼠的生化和行为数据，这些化合物中的几种被表征为中枢作用的DA自身受体拮抗剂。发现在3位（即相对于哌啶环为间位）具有高基团偶极矩的芳族取代基且被丙基N-取代的（S）-苯基哌啶在体内对多巴胺的合成和周转具有高活性。然而，它们不会引起强烈的活动减退或僵住症。有趣的是，发现体内活性最高的化合物在体外对DA D2和D3受体仅表现出低亲和力。此外，已制备并对7-三氟甲磺酸盐取代的八氢苯并[f]喹啉和6-三氟甲磺酸盐取代的六氢-1H-苯并[e]吲哚进行了药理学评估。发现这些刚性结构的反式异构体表现出与柔性苯基哌啶相似的药理学特征。发现相应的顺式异构体在体内无活性。
