title: Conformationally constrained CCK4 analogues incorporating IBTM and BTD beta-turn mimetics.
abstract: To test whether a turnlike arrangement is involved in the bioactive conformation of CCK4 analogues upon CCK1 receptor recognition, we describe the preparation of two series of CCK4 derivatives, in which the central dipeptide Met-Asp has been replaced by recognized beta-turn mimetics {(2S,5S,11bR)- and (2R,5R,11bS)-2-amino-5-carboxy-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (IBTM) and beta-turn dipeptide, 2-oxo-7-thio-1-azabicyclo[4.3.0]nonane (BTD)}. The incorporation of the indolizinoindole IBTM type II beta-turn mimetic is preferred over its type II' counterpart for efficient CCK1 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 CCK1 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 pi-pi 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 CCK1 receptor antagonists, exemplified by compounds 8a and 8b, emerges among these IBTM-containing derivatives.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martín-Martínez
authors.forename: Natalia
authors.initials: N
authors.lastname: De la Figuera
authors.forename: Miriam
authors.initials: M
authors.lastname: Latorre
authors.forename: M Teresa
authors.initials: MT
authors.lastname: García-López
authors.forename: Edurne
authors.initials: E
authors.lastname: Cenarruzabeitia
authors.forename: Joaquín
authors.initials: J
authors.lastname: Del Río
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002540:Cerebral Cortex / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry*; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D051381:Rats; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C507718:2-oxo-7-thio-1-azabicyclo(4.3.0)nonane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004151:Dipeptides; D007211:Indoles; D008024:Ligands; D043886:Receptor, Cholecystokinin A; C448863:S-IBTM; D013758:Tetragastrin; D000681:Amylases