Analogs of Ac-CCK-7 incorporating dipeptide mimics in place of Met28-Gly29.

A series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met28-Gly29-Trp-Met-Asp- Phe-NH2, (1)] were prepared in which the Met28-Gly29 dipeptide was replaced by omega-aminoalkanoic acids. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors, respectively, and for anorectic activity after intraperitoneal administration to rats. The analog incorporating 4-aminobutanoic acid (5) was only 8 times less potent than 1 in the pancreatic binding assay, was more potent in the striatal binding assay, and was more potent than 1 in reducing food intake in rats.

Structure activity studies of tryptophan30 modified analogs of Ac-CCK-7.

Cholecystokinin represents a family of gut hormones which among other activities, have been proposed to participate in satiety signaling. Ac-CCK-7[Ac-Tyr(SO3H)-Met-Gly-Trp30-Met-Asp-Phe-NH2 (2)] possesses the full spectrum of activity and potency of the intact hormone; thus analogs of 2 may be useful as anorectic agents. A series of derivatives has been prepared in which the tryptophan indole moiety of 2 has been modified.

Structure activity of C-terminal modified analogs of Ac-CCK-7.

Previous work indicates that both the C-terminal phenylalanine amide and the tryptophan moieties of cholecystokinin (CCK) are critical pharmacophores for interaction with either the A or B receptor subtypes. We have examined a series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe33-NH2] (2) in which the phenyl ring of the C-terminal Phe-NH2 has been modified. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors respectively and for anorectic activity after intraperitoneal administration to rats.