RESUMO
Several analogues of the neuroleptic agent butaclamol, having modifications in the ring E region of the molecule, have been synthesized. Pharmacological evaluation identified two of the analogues as being equipotent to butaclamol, namely, anhydrobutaclamol (8) and deoxybutaclamol (9a). The molecular structures of both the active and inactive analogues were analyzed and the results have been used for mapping the central dopamine receptor. The existence of a previously proposed lipophilic accessory binding site on the receptor macromolecule has been confirmed. Its minimum dimensions, as well as its locus with respect to the primary binding sites, have been defined. A receptor model incorporating the above features is proposed.
Assuntos
Butaclamol/metabolismo , Dibenzocicloeptenos/metabolismo , Receptores Dopaminérgicos/metabolismo , Agressão/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Butaclamol/análogos & derivados , Butaclamol/síntese química , Butaclamol/farmacologia , Catalepsia/induzido quimicamente , Dextroanfetamina/antagonistas & inibidores , Epinefrina/antagonistas & inibidores , Epinefrina/toxicidade , Humanos , Masculino , Métodos , Camundongos , Modelos Moleculares , Conformação Molecular , Conformação Proteica , Ratos , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Several analogues of the neuroleptic agent butaclamol having modifications in the rings A/B region of the molecule have been synthesized. Pharmacological evaluation identified the benzo[5,6]cyclohepta analogue 2b, isobutaclamol, as being equipotent to butaclamol. The molecular structure of this compound has been analyzed, and the results have been used for mapping the central dopamine receptor. A planar catechol primary binding site, composed of alpha and beta regions, has been identified and its minimal dimensions deduced. Its locus with respect to the nitrogen location site and its complementary hydrogen bond donor site has been specified. Using a Cartesian coordinate system, a receptor model is proposed which incorporates the above-mentioned features. The receptor model has been used to rationalize the observed chirality of the central dopamine receptor.
Assuntos
Butaclamol/metabolismo , Dibenzocicloeptenos/metabolismo , Receptores Dopaminérgicos/metabolismo , Agressão/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Butaclamol/análogos & derivados , Butaclamol/síntese química , Butaclamol/farmacologia , Catalepsia/induzido quimicamente , Dextroanfetamina/antagonistas & inibidores , Epinefrina/antagonistas & inibidores , Epinefrina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Conformação Proteica , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of 37 1-ethyl- and 1-n-propyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acids bearing one, or two, substituents on the benzene ring has been synthesized via the acid-catalyzed condensation of a substituted tryptophol with ethyl propionylacetate or ethyl butyrylacetate. Antiinflammatory and ulcerogenic effects were examined and the results show that 1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acid (etodolic acid, USAN) is a potent agent, particularly active against a chronic rat model of inflammation (ED50 0.7 + 1-0.1 mg/kg po in the adjuvant arthritis model) and which has a relatively low acute ulcerogenic potential in the same species.
