title: New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R).
abstract: The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK(1)-R antagonists.
authors: Department of Chemical and Pharmaceutical Sciences, University of Trieste, P.le Europa 1, 34127 Trieste, Italy.
authors: Michela V
authors: MV
authors: Pavan
authors: Lucia
authors: L
authors: Lassiani
authors: Federico
authors: F
authors: Berti
authors: Giorgio
authors: G
authors: Stefancich
authors: Alessia
authors: A
authors: Ciogli
authors: Francesco
authors: F
authors: Gasparrini
authors: Laura
authors: L
authors: Mennuni
authors: Flora
authors: F
authors: Ferrari
authors: Chantal
authors: C
authors: Escrieut
authors: Esther
authors: E
authors: Marco
authors: Francesco
authors: F
authors: Makovec
authors: Daniel
authors: D
authors: Fourmy
authors: Antonio
authors: A
authors: Varnavas
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D019556:COS Cells; D002540:Cerebral Cortex / Q000378:metabolism; D002522:Chlorocebus aethiops; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C568460:2-(2-((1H-indole-2-carbonyl)amino)benzoylamino)-4-phenylbutyric acid; D000613:Aminobutyrates; D006571:Heterocyclic Compounds; D007211:Indoles; D043886:Receptor, Cholecystokinin A; C492564:VL-0395; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D012844:Sincalide