Anthranilic acid based CCK1 antagonists: the 2-indole moiety may represent a "needle" according to the recent homonymous concept.
Recently we described an innovative class of non-peptide CCK(1) antagonists keeping appropriate pharmacophoric groups on the anthranilic acid employed as a molecular scaffold. The lead compound obtained, VL-0395, characterized by the presence of Phe and the 2-indole moiety at the C- and N-termini of anthranilic acid, respectively, is endowed with submicromolar affinity towards CCK(1) receptors. Thus, we have prepared and tested on CCK receptors a library of VL-0395 analogues in order to investigate the precise topological and essential key interactions of the 2-indole group of the lead with the CCK(1) receptor. The obtained results confirm that this group establishes very specific interactions with this receptor sub-site and may be viewed as a "needle" group.
Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. varnavas@units.it
Antonio
A
Varnavas
Lucia
L
Lassiani
Valentina
V
Valenta
Federico
F
Berti
Andrea
A
Tontini
Laura
L
Mennuni
Francesco
F
Makovec
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D006168:Guinea Pigs; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010179:Pancreas / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D007211:Indoles; D043886:Receptor, Cholecystokinin A; C492564:VL-0395; D062367:ortho-Aminobenzoates