Anthranilic acid derivatives: a new class of non-peptide CCK1 receptor antagonists.
Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.
Varnavas
Antonio
A
Department of Pharmaceutical Sciences, University of Trieste, P.le Europa 1, 34127 Trieste, Italy. varnavas@univ.trieste.it
Lassiani
Lucia
L
Valenta
Valentina
V
Berti
Federico
F
Mennuni
Laura
L
Makovec
Francesco
F
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002855:Chromatography, Thin Layer; D006168:Guinea Pigs; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
D007202:Indicators and Reagents; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D062367:ortho-Aminobenzoates