The agonist SR 146131 and the antagonist SR 27897 occupy different sites on the human CCK1 receptor

1-[2-(4-(2-Chlorophenyl)thiazol-2-yl) aminocarbonyl indoyl] acetic acid (SR 27897) is an effective CCK, receptor antagonist, while the structurally re lated molecule 2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)-t hiazol-2-ylcarbomoyl]-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) CCK, recep tor, we have carried out binding and activity studies with 33-point mutated receptors. Only six mutants showed altered [H-3]SR 27897 binding propertie s, Lys(115), Lys(187), Phe(198), Trp(209), Leu(214) and Asn(333). In contra st, numerous mutations throughout the receptor either reduced SR 146131 ago nist potency, Phe(97), Gly(122), Phe(198), Trp(209), Ile(229), Asn(333) Arg (336) and Leu(356) Or increased it, Tyr(48), Cys(94), Asn(98), Leu(217) and Ser(359). Only mutations of Phe(198), Trp(209) and Asn(333) affected both SR 27897 and SR 146131 binding or activity, The collated information was us ed to construct molecular models of SR 27897 and SR 146131 bound to the hum an CCK, receptor. The clear difference in the binding sites of SR 27897 and SR 146131 offers a molecular explanation for their contrasting pharmacolog ical characteristics. (C) 2000 Elsevier Science B.V. All rights reserved.