The agonist SR 146131 and the antagonist SR 27897 occupy different sites on the human CCK(1) receptor |
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Authors: | Gouldson P Legoux P Carillon C Delpech B Le Fur G Ferrara P Shire D |
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Affiliation: | Sanofi-Synthelabo Recherche, Centre de Labège, Labège-Innopole, Voie No. 1, BP 137, 31676 Labège Cedex, France |
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Abstract: | 1-[2-(4-(2-Chlorophenyl)thiazol-2-yl) aminocarbonyl indoyl] acetic acid (SR 27897) is an effective CCK1 receptor antagonist, while the structurally related molecule 2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethyl-indol-1-yl-1-acetic acid (SR 146131) is a highly potent and specific agonist for the same receptor. To discover how the two molecules interact with the human cholecystokinin (CCK) CCK1 receptor, we have carried out binding and activity studies with 33-point mutated receptors. Only six mutants showed altered [3H]SR 27897 binding properties, Lys115, Lys187, Phe198, Trp209, Leu214 and Asn333. In contrast, numerous mutations throughout the receptor either reduced SR 146131 agonist potency, Phe97, Gly122, Phe198, Trp209, Ile229, Asn333, Arg336 and Leu356 or increased it, Tyr48, Cys94, Asn98, Leu217 and Ser359. Only mutations of Phe198, Trp209 and Asn333 affected both SR 27897 and SR 146131 binding or activity. The collated information was used to construct molecular models of SR 27897 and SR 146131 bound to the human CCK1 receptor. The clear difference in the binding sites of SR 27897 and SR 146131 offers a molecular explanation for their contrasting pharmacological characteristics. |
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Keywords: | CCK1 receptor Binding site Modelling SR 27897 SR 146131 |
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