Anthranilic acid based CCK1 receptor antagonists: preliminary investigation on their second "touch point".
In this phase of structure-affinity relationship study of VL-0395, a new anthranilic acid based CCK1 selective antagonist, we propose a series of unnatural aminoacidic derivatives. The result of this work is the identification of a new CCK ligand, which possesses an affinity (IC50 = 35 nm) one order of magnitude greater than the lead and, as a general rule, it points out how the hypothesized receptorial pocket which accommodates the Phe residue allows much more structural modification than that interacting with the N-terminal group. Hence, the modification of the C-terminal pharmacophoric group of our lead VL-0395 can not only enhance the affinity of anthranilic acid derivatives but can modulate the selectivity for one CCK receptor subtype or afford mixed antagonists.
Varnavas
Antonio
A
Department of Pharmaceutical Sciences, University of Trieste, P.le Europa 1, 34127 Trieste, Italy. varnavas@units.it
Lassiani
Lucia
L
Valenta
Valentina
V
Mennuni
Laura
L
Makovec
Francesco
F
Hadjipavlou-Litina
Dimitra
D
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008566:Membranes / Q000502:physiology; D010179:Pancreas / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010865:Pilot Projects; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D007211:Indoles; D043886:Receptor, Cholecystokinin A; C492564:VL-0395; D062367:ortho-Aminobenzoates; D010649:Phenylalanine