INTERSPECIES AND INTRASPECIES POLYMORPHISMS IN THE CHOLECYSTOKININ-B GASTRIN RECEPTOR ALTER DRUG EFFICACY/

The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major targe t for drug development because of its postulated role in modulating an xiety, memory, and the perception of pain, Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype, These drugs include the pe ptide-derived compound PD135,158 as well as the nonpeptide benzodiazep ine-based ligand, L-740,093 (S enantiomer). We now report that the max imal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among sp ecies homologs of the CCK-BR, Further analysis reveals that the observ ed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective specie s homologs, This interspecies variability in ligand efficacy introduce s the possibility of species differences in receptor-mediated function , an important consideration when selecting animal models for preclini cal drug testing, The finding that even single amino acid substitution s can significantly affect drug efficacy prompted us to examine ligand -induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; E-288 --> K). When examined using the E-288 --> K receptor, the efficacies of both PD135 ,158 and L-740,093 (S) were markedly increased compared with values ob tained with the wild-type human protein, These observations suggest th at functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.