Modification of "peptoid" CCK-B antagonists to probe requirements for CCK-B agonist activity

This paper describes the use of the non-peptidal N-(2-adamantyloxycarbonyl)-alpha-methyl tryptophan phenylethylamide template of the "peptoid" CCK B antagonist compounds 1 as a basis to probe the functional group requirements of the CCK B receptor in order to produce an agonist response. Comparison of the peptoid template with inter-group distances in a fully extended conformation of the endogenous CCK-B agonist CCK 30-33 led to the design of a series of compounds 2 containing additional Ph, COOH and CONH2, functions at distances from the Trp indole ring that are able to mimic those in the natural ligand. The effect of these modifications was then assessed by measurement of CCK B binding affinities and potential agonist efficacy was investigated by comparison with contraction of guinea-pig isolated stomach corpus muscle strip stimulated by the CCK-B agonist pentagastrin. All compounds showed sub-micromolar binding affinities with each series displaying discernible dependence on intermediate chain length. All compounds (except 2f) were shown to be good CCK B antagonists; no compounds showed significant agonist activity up to a concentration of 1 microM.