Rationally designed "dipeptoid" analogues of CCK. A Free-Wilson/Fujita-Ban analysis of some alpha-methyltryptophan derivatives as CCK-B antagonists.

A Free-Wilson/Fujita-Ban (FW/FB) analysis is reported on 36 "dipeptoid" antagonists of the CCK-B receptor. This series of compounds includes [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1] dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]- 4-oxobutanoic acid (CI-988, 1, Figure 1), the first rationally designed non-peptide antagonist of a neuropeptide receptor. The analysis treats the compounds in three parts: the N-terminus, variants on the tryptophan moiety, and the C-terminus. A highly significant correlation was found (n = 36, r2 = 0.97, s = 0.22, F = 57, p = 2 x 10(-8)), suggesting that these three domains of these compounds contribute to binding affinity independently of each other, and are therefore additive in their effects on receptor affinity. The relative free-energies of binding of the individual substituents are calculated from the coefficients of the regression equation. The substitution of D-alpha-methyltryptophan for L-tryptophan increases the free-energy of binding by 3.5 kcal mol-1. This increase in binding energy is explained by a 300-fold difference in conformational entropy between the methylated and desmethyl analogues.