This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1 3,7]dec-2-yl [R-(R*,S*)]-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carbamate (4) (CCK-B IC50 = 852 nM), and tricyclo[3.3.1.1 3,7]dec-2-yl (R)-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (23) (CCK-B IC50 = 32 nM) is replaced by 11 different amide replacements. These replacements are the methyleneamino (CH2NH), the reverse amide (NHCO), the ester (COO), the N-methylamide (CONMe), the thioamide (CSNH), the N-acetylmethyleneamino (CH2NAc), the cis double bond (CHCH), the ethylene (CH2CH2), the thiolester (COS), the hydroxyethylene (CHOHCH2), and a 4,5-dihydro-1,3-thiazole. Most of the replacements have weaker affinity and reduced selectivity for the CCK-B receptor than the parent amide. However, this affinity can be improved by appending a fumarate side chain to the phenethyl group, e.g. tricyclo[3.3.1.1 3,7]dec-2-yl-3-(1H-indol-3-yl-methyl)-3-methyl-4,9-dioxo-7-phenyl-5,13-dioxa-2,8-diazatetradec-10-enoate (36) (CCK-B IC50 = 38.8 nM). Replacement of the amide of compound 4 with a 4,5-dihydro-1,3-thiazole gives tricyclo[3.3.1.1 3,7]dec-2-yl [1-[4,5-dihydro-4-(phenylmethyl)-2-thiazolyl]-2-(1H-indol-3-yl)ethyl]carbamate (5), which is selective for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM, ratio = 21). The methyleneamino and hydroxyethylene replacements, which have been used elsewhere as transition-state inhibitors of enzymes, are poor mimics of the amide in these CCK-B receptor ligands. Some of the steric, lipophilic, and hydrogen bonding properties of amide replacements incorporated into the simple amide, N-methylacetamide, have been quantified with the aid of molecular modeling. These data will contribute to the rational selection of amide bond replacements in other substrates.
