beta-turned dipeptoids as potent and selective CCK1 receptor antagonists

To improve our knowledge of the bioactive conformation of CCK1 antagonists, we previously described that replacement of the alpha-MeTrp residue of dip eptoids with the (2S,5S,11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole -5-carboxylate (IBTM) skeleton, a probed type II' beta-turn mimetic, led to restricted analogues (2S,5S,11bR,1'S)- and (2S,5S,11bR, 1'R)-2-(benzyloxyc arbonyl)amino-5-[1'-benzyl-2'-(carboxy)ethyl]carbamoyl-3-oxo-2,3,5,6,11,11b -hexahydro-1H-indolizino-[8,7-b]indole, 1a,b, showing high binding affinity and selectivity for CCK1 receptors. In this report, we describe the synthe sis and binding profile of new analogues of compounds 1 designed to explore the importance of the C-terminal residue and of the type of beta-turn on t he receptor binding affinity and selectivity. Structure-affinity relationsh ip studies show that a C-terminal free carboxylic acid and an S configurati on of the Phe and beta Hph residues are favorable for CCK1 receptor recogni tion. Moreover, selectivity for this receptor subtype is critically affecte d by the beta-turn type. Thus, while compounds 15a and 16a, containing the (2S,5S,11bR)- and (2R,5R, 11bS)-IBTM frameworks, respectively, are both end owed with nanomolar affinity for CCK1 receptors, restricted dipeptoid deriv ative 15a, incorporating the type II' IBTM mimetic, shows approximately 6-f old higher CCK1 selectivity than analogue 16a, with the type II mimetic. Fr om these results, we propose that the presence of a beta-turn-like -conform ation within the peptide backbone of dipeptoids could contribute to their b ioactive conformation at the CCK1 receptor subtype. Concerning functional a ctivity, -compounds 15a and 16a behave as CCK1 receptor antagonists.