RATIONALLY DESIGNED DIPEPTOID ANALOGS OF CHOLECYSTOKININ (CCK) - N-TERMINAL STRUCTURE AFFINITY RELATIONSHIPS OF ALPHA-METHYL-TRYPTOPHAN DERIVATIVES

The structure-affinity relationships (SAR) between the N-terminii of a series of alpha-methyl-tryptophanylphenethylamide derivatives and the cholecystokinin (CCK) B receptor are discussed. A series of compounds with the general formula R-X-alpha-methyl-tryptophanylphenethylamide was prepared, where R is a cycloalkyl, a bicycloalkyl or a tricycloalkyl group and X is a urethane, thiourethane, amide, urea or a sulphinamide linking group. The CCK-B receptor binding affinities of these are discussed. The SAR form part of a systematic program for the rational design of 'dipeptoid' analogues of the neuropeptide CCK. Beginning with 1,1-dimethylpropyl (+/-)-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (IC50 = 4720 nM on CCK-B binding affinity) the N-terminal moiety was systematically changed for groups of varying size, shape and lipophilicity until the optimal N-terminal group was obtained and the favoured linking group chosen, resulting in the compound tricyclo[3.3.1.1(3,7)]dec-2-yl(R)-[(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate with an IC50 = 32 nM on CCK-B receptor binding affinity.