1-Benzazepin-2-one calcium channel blockers--VI. Receptor-binding model and possible relationship to desmethoxyverapamil.
Bioorg Med Chem
; 1(4): 285-307, 1993 Oct.
Article
em En
| MEDLINE
| ID: mdl-8081860
ABSTRACT
We have prepared a series of potent antihypertensive 1-benzazepin-2-one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem 2. Structural studies and the preparation of conformationally constrained analogs of 1-benzazepin-2-ones have led us to postulate a receptor-bound conformation for both 1 and 2. We believe that these compounds bind to the calcium channel protein in an MI ("inboard") binding conformation in which the amine of the side chain is placed over the heptagonal benzazepione ring and in close proximity to the phenyl methyl ether pharmacophore. This receptor-bound conformation places the side chain amine and methyl ether pharmacophores in the same spatial relationship as 3-methoxyphenylethalamine. Combined with our SAR, this binding model rationalizes literature findings that desmethoxyverapamil can demonstrate pharmacology typical of both phenylalkylamine (PA) and benzothiazepinone (DTZ) calcium channel blockers. Simple experiments are proposed to test the hypothesis that desmethoxyverapamil can bind at the benzothiazepinone site on the calcium channel.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzazepinas
/
Bloqueadores dos Canais de Cálcio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
1993
Tipo de documento:
Article