Synthesis of new anthranilic acid dimer derivatives and their evaluation on CCK receptors.
We have described previously an innovative bond disconnection strategy of asperlicin, a naturally occurring CCK receptor antagonist, leading to anthranilic acid dimer and tryptophan synthons. We have also demonstrated that when the tryptophan residue is connected to the C- or N-terminal sides of the anthranilic acid dimer, compounds with similar micromolar CCK-A receptor affinities are obtained. In order to investigate the binding effects of different N-terminal substitution, in this paper we describe a new series of anthranilic acid dimer derivatives, characterized by the presence of the tryptophan residue in the C-terminus of the dimer. Among the compounds synthesized, the N-1H-indol-3-propionyl derivative exhibited an improved, at the micromolar range, affinity for the CCK-A receptor in comparison to that of either, the N-unsubstituted derivative and asperlicin. The lead compound emerging from this key step of our investigation represents the new starting point for the development of a new class of CCK-A receptor ligands.
Varnavas
A
A
Department of Pharmaceutical Sciences, University of Trieste, Italy. varnavas@univ.trieste.it
Lassiani
L
L
Valenta
V
V
D000818:Animals; D019281:Dimerization; D004341:Drug Evaluation; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*
D011949:Receptors, Cholecystokinin; D062367:ortho-Aminobenzoates; C031385:anthranilic acid