Conformationally constrained CCK4 analogues incorporating IBTM and BTD β-turn mimetics

To test whether a turnlike arrangement is involved in the bioactive conformation of CCK4 analogues upon CCK 1 receptor recognition, we describe the preparation of two series of CCK4 derivatives, in which the central dipeptide Met-Asp has been replaced by recognized /3-turn mimetics {(2S,5S,11bR)- and (2R,5R,11bS)-2-amino-5-carboxy-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (IBTM) and β-turn dipeptide, 2-oxo-7-thio-1-azabicyclo[4.3.0]nonane (BTD)}. The incorporation of the indolizinoindole IBTM type II /?-turn mimetic is preferred over its type II' counterpart for efficient CCK 1 receptor recognition, while BTD derivatives were completely inactive. The structure-conformation-activity relationship study in the IBTM series has shown some essential requirement of these CCK4 derivatives to favorably interact with CCK 1 receptors: (a) the adoption of turnlike conformations, (b) the presence of an 1-Phe residue and a C-terminal carboxamide moiety, and (c) the indole ring of the IBTM skeleton. Moreover, the existence of π-π interactions between the phenyl ring of D-Phe residues and the indole ring of IBTM framework is detrimental for binding affinity. A series of potent and selective CCK 1 receptor antagonists, exemplified by compounds 8a and 8b, emerges among these IBTM-containing derivatives.