β-Turned Dipeptoids as Potent and Selective CCK<INF>1</INF> Receptor Antagonists

To improve our knowledge of the bioactive conformation of CCK<INF>1</INF> antagonists, we previously described that replacement of the α-MeTrp residue of dipeptoids with the (2S,5S,11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carboxylate (IBTM) skeleton, a probed type II‘ β-turn mimetic, led to restricted analogues (2S,5S,11bR,1‘S)- and (2S,5S,11bR,1‘R)-2-(benzyloxycarbonyl)amino-5-[1‘-benzyl-2‘-(carboxy)ethyl]carbamoyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, <BO>1a</BO>,<BO>b</BO>, showing high binding affinity and selectivity for CCK<INF>1</INF> receptors. In this report, we describe the synthesis and binding profile of new analogues of compounds <BO>1</BO> designed to explore the importance of the C-terminal residue and of the type of β-turn on the receptor binding affinity and selectivity. Structure−affinity relationship studies show that a C-terminal free carboxylic acid and an S configuration of the Phe and βHph residues are favorable for CCK<INF>1</INF> receptor recognition. Moreover, selectivity for this receptor subtype is critically affected by the β-turn type. Thus, while compounds <BO>15a</BO> and <BO>16a</BO>, containing the (2S,5S,11bR)- and (2R,5R,11bS)-IBTM frameworks, respectively, are both endowed with nanomolar affinity for CCK<INF>1</INF> receptors, restricted dipeptoid derivative <BO>15a</BO>, incorporating the type II‘ IBTM mimetic, shows approximately 6-fold higher CCK<INF>1</INF> selectivity than analogue <BO>16a</BO>, with the type II mimetic. From these results, we propose that the presence of a β-turn-like conformation within the peptide backbone of dipeptoids could contribute to their bioactive conformation at the CCK<INF>1</INF> receptor subtype. Concerning functional activity, compounds <BO>15a</BO> and <BO>16a</BO> behave as CCK<INF>1</INF> receptor antagonists.