A concerted study using binding measurements, X-ray structural data, and molecular modeling on the stereochemical features responsible for the affinity of 6-arylpyrrolo[2,1-d][1,5]benzothiazepines toward mitochondrial benzodiazepine receptors.
J Med Chem
; 38(23): 4730-8, 1995 Nov 10.
Article
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| MEDLINE
| ID: mdl-7473601
ABSTRACT
The 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives have been recently proposed as a new class of ligands specific for the mitochondrial benzodiazepine receptor (Fiorini et al. J. Med. Chem. 1994, 37, 1427-1438) (Greco et al. J. Med. Chem. 1994, 37, 4100-4108). In this paper we report the X-ray crystallographic structures of three potent (1-3) and two inactive (4 and 5) previously described benzothiazepines, as well as binding affinity constants for two newly assayed analogs in which the acyloxy side chain was replaced by a methoxy group (6) or removed (7). Structure-affinity relationships and molecular mechanics calculations performed using crystal structures as references have led to a revised 3D pharmacophore model accounting for all the data available up until now. Interestingly, the hypothetical receptor-bound conformations of 1-3 display a considerable degree of similarity with their crystal geometries. Additional calculations have confirmed that the poor affinities of benzothiazepines bearing an aroyloxy group (4 and 5) should be ascribed to the steric and/or electronic features of the side chain aryl moieties rather than to unfavorable conformational properties.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirroles
/
Tiazepinas
/
Difracción de Rayos X
/
Modelos Moleculares
/
Receptores de GABA-A
/
Mitocondrias
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1995
Tipo del documento:
Article
País de afiliación:
Italia