Binding of 5H-Dibenzo[b,e][1,4]diazepine and Chiral 5H-Dibenzo[a,d]cycloheptene Analogs of Clozapine to Dopamine and Serotonin Receptors

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.

Esquizofrenia: quarenta anos da hipótese dopaminérgica sob a ótica da Química Medicinal

“…Devido ao fato de a clozapina (5) ter demonstrado um perfil terapêutico diferenciado dos antipsicóticos clássicos, seu núcleo [8-cloro-11-(4-metil-1-piperazinil)-5H-dibenzo [1,4] diazepina] foi extensamente estudado, visando-se obter compostos que apresentassem semelhante perfil terapêutico sem, contudo, apresentar seus efeitos colaterais [62][63][64] . O emprego de estratégias racionais de modificação molecular sobre a estrutura da clozapina (5), incluindo trocas isotéricas, simplificações estruturais, contrações de anel, não lograram na obtenção de análogos com perfis de bioatividade e toxicidade significativamente superiores ao protótipo [63][64][65] , mas permitiram hierarquizar as sub-unidades moleculares de maior relevância para a atividade central, tornando possível a obtenção de novos derivados heterocíclicos, e.g.…”

The synthesis of novel hexahydrodibenzo[b,e][1,4]diazepin-1-one derivatives

“…Out of the class of tricyclic dibenzo [b,е] [1,4]diazepines, the anxiolytic Clozepene, 1 the antidepressant Dibenzepine, 2 and also the drug Pirenzepine, which is used for ulcer treatment, 3 are the most widely-applied in medicine. Today research into tricyclic 1,4-diazepines is connected with the modification of their structure furnishing, first of all, potential antipsychotic drugs.…”

“…Today research into tricyclic 1,4-diazepines is connected with the modification of their structure furnishing, first of all, potential antipsychotic drugs. 4,5 Functionalized diphenylamines containing amino and ester groups in o-positions of the phenyl rings serve as the initial compounds for the synthesis of dibenzo [b,е] [1,4]diazepines. 6,7 Also partially hydrogenated dibenzodiazepines obtained from 3-aminoenones of cyclohexene-1,3-dione and aldehydes were described in references 8-12.…”

“…Diazepines 1 were also obtained via one-pot condensation 13 by sequential addition of reagents, namely: by reflux of dimedone with o-PDA in 2-propanol in the presence of a catalytic amount of acetic acid for 40 minutes followed by the addition of aldehyde. We have reported the synthesis of two compounds of the 11-aroylhexahydrodibenzo[b,е] [1,4]diazepin-1-ones series (R = COAr), when arylglyoxals were used instead of benzaldehydes. The purpose of this paper was to research the class of hexahydrodibenzo [b,е] [1,4]diazepin-1-ones by varying the structure of cyclohexane-1,3-diones, arylglyoxals and also to study the transformations of the compounds synthesized in reactions specific for secondary amines.…”

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Abstract 3,4,5,10,е][1,4]diazepin-1-ones are obtained by reaction of 3-(2-aminophenylamino)cyclohex-2-en-1-ones with arylglyoxal hydrates in 2-propanol. Also, several of their chemical properties (alkylation, acetylation, nitrosation) were investigated.

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