氯氮平的5H-二苯并[b,e][1,4]二氮杂䓬及手性5H-二苯并[a,d]环庚烯类似物与多巴胺和5-羟色胺受体的结合

Binding of 5H-dibenzo[b,e][1,4]diazepine and chiral 5H-dibenzo[a,d]cycloheptene analogues of clozapine to dopamine and serotonin receptors.

作者信息

Phillips S T, de Paulis T, Baron B M, Siegel B W, Seeman P, Van Tol H H, Guan H C, Smith H E

机构信息

Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.

出版信息

J Med Chem. 1994 Aug 19;37(17):2686-96. doi: 10.1021/jm00043a008.

DOI:10.1021/jm00043a008

PMID:8064797

Abstract

5H-Dibenzo[b,e][1,4]diazepine, dibenz[b,f]oxepin, and 5H-dibenzo[a,d]cycloheptene analogues of clozapine [8-chloro-11-(4-methylpiperazino)-5H- dibenzo[b,e][1,4]diazepine] were evaluated for their binding affinity to dopamine D-1, D-2, and D-4 and serotonin S-2A (5-HT2A), S-2C (5-HT2C) and S-3 (5-HT3) receptors. The diazepine analogues display selective binding to the dopamine D-4 and serotonin S-2A receptors similar to that of clozapine, but none has a dopamine D-4 selectivity (Ki for the dopamine D-2A receptor/Ki for the dopamine D-4 receptor) greater than that of clozapine. All of the oxepin analogues also show substantial binding to the dopamine D-4 and serotonin S-2A receptors with 10-(4-methylpiperazino)dibenz[b,f]oxepin having a dopamine D-4 selectivity greater than that of clozapine. Some of the 5H-dibenzo-[a,d]cycloheptene analogues also show strong binding to both the dopamine D-4 and serotonin S-2A receptors, 5-methyl-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene having a dopamine D-4 selectivity of 7.8 as compared to 10 for clozapine but a serotonin S-2A selectivity (Ki for the dopamine D-2 receptor/Ki for the serotonin S-2A receptor) of 2.0 as compared to 28 for clozapine. The serotonin S-2A selectivity of 2-chloro-10-(4-methylpiperazino)-5H-dibenzo[a,d]-cycloheptene++ + is 200. As an extension of these studies, chiral 5-substitute 10-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-5H-dibenzo[a,d]cyclohept ene analogues show a substantial enantiospecificity toward dopamine and serotonin receptor subtypes, (R)-(-)-5-methyl compound having a 2-fold higher dopamine D-4 selectivity than its (S)-(+) enantiomer as the result of enhanced binding to the dopamine D-4 receptor rather than diminished binding to the dopamine D-2 receptor. (pRa,pSb)-(+)-5-(2-Propylidene)-10-(1,2,3,6-tetrahydro-1-met hyl- 4-pyridinyl)-5H-dibenzo[a,d]cycloheptene is 17 times more active in binding to the dopamine D-4 receptor than is its pSa,pRb enantiomer while being only 1.5 times more active in binding to the dopamine D-2 receptor.

摘要

对氯氮平[8-氯-11-(4-甲基哌嗪基)-5H-二苯并[b,e][1,4]二氮杂卓]的5H-二苯并[b,e][1,4]二氮杂卓、二苯并[b,f]氧杂卓和5H-二苯并[a,d]环庚烯类似物进行了评估，以研究它们对多巴胺D-1、D-2和D-4以及5-羟色胺S-2A（5-HT2A）、S-2C（5-HT2C）和S-3（5-HT3）受体的结合亲和力。二氮杂卓类似物对多巴胺D-4和5-羟色胺S-2A受体表现出与氯氮平相似的选择性结合，但没有一种具有比氯氮平更高的多巴胺D-4选择性（多巴胺D-2A受体的Ki/多巴胺D-4受体的Ki）。所有氧杂卓类似物也显示出与多巴胺D-4和5-羟色胺S-2A受体有大量结合，其中10-(4-甲基哌嗪基)二苯并[b,f]氧杂卓的多巴胺D-4选择性高于氯氮平。一些5H-二苯并[a,d]环庚烯类似物也显示出与多巴胺D-4和5-羟色胺S-2A受体都有强结合，5-甲基-10-(4-甲基哌嗪基)-5H-二苯并[a,d]环庚烯的多巴胺D-4选择性为7.8，而氯氮平为10，但5-羟色胺S-2A选择性（多巴胺D-2受体的Ki/5-羟色胺S-2A受体的Ki）为2.0，而氯氮平为28。2-氯-10-(4-甲基哌嗪基)-5H-二苯并[a,d]环庚烯的5-羟色胺S-2A选择性为200。作为这些研究的扩展，手性5-取代的10-(1,2,3,6-四氢-1-甲基-4-吡啶基)-5H-二苯并[a,d]环庚烯类似物对多巴胺和5-羟色胺受体亚型表现出显著的对映体特异性，(R)-(-)-5-甲基化合物由于增强了与多巴胺D-4受体的结合而不是减少了与多巴胺D-2受体的结合，其多巴胺D-4选择性比其(S)-(+)对映体高2倍。(pRa,pSb)-(+)-5-(2-亚丙基)-10-(1,2,3,6-四氢-1-甲基-4-吡啶基)-5H-二苯并[a,d]环庚烯与多巴胺D-4受体结合的活性比其pSa,pRb对映体高17倍，而与多巴胺D-2受体结合的活性仅高1.5倍。