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<INF>1</INF> receptor recognition, we describe the preparation of two series of CCK4 derivatives, in which the central dipeptide Met-Asp has been replaced by recognized β-turn mimetics {(2S,5S,11bR)- and (2R,5R,11bS)-2-amino-5-carboxy-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (IBTM) and β-turn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 β-turn mimetic is preferred over its type II‘ counterpart for efficient CCK<INF>1</INF> 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<INF>1</INF> receptors:  (a) the adoption of turnlike conformations, (b) the presence of an l-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 <SCP>d</SCP>-Phe residues and the indole ring of IBTM framework is detrimental for binding affinity. A series of potent and selective CCK<INF>1</INF> receptor antagonists, exemplified by compounds <BO>8a</BO> and <BO>8b</BO>, emerges among these IBTM-containing derivatives.