SELECTIVE STIMULATION OF INSULIN SECRETION BY CCK-4 ANALOGUES HAVING N-TERMINAL MODIFICATIONS FAIYAZ AHMAD *, BIJOY KUNDU **, MOHAMMED M. KHAN *, ANIL K. RASTOGI *, KRISHNA B. MATHUR **, JALIL R. KIDWAI * Division of Biochemistry * and Biopolymers **, Central Drug Research Institute, Lucknow, India Peptide hormones such as the gut hormones gastrin and cholecystokinin, play an important role as neuroregulators. Cholecystokinin has been impli- cated as a neurotransmitter influencing hormonal release from the islets. Amongst various cholecystokinins, CCK-4 was found to be considerably more effective in releasing islet hormones 9. Several congeners of CCK-4, in which structural modifications were intro- duced at C and N-termini of the tetrapeptide were synthesized in our labora- tory with a view to get peptides that would selectively stimulate the release of insulin without affecting the release of other islet hormones 1,~ and thus could possibly be employed for the treatment of type II diabetes mellitus. As an extension of these structure activity relationship studies, three novel congeners of CCK-4 were synthesized by us recently. In these tetrapeptides, Trp of CCK-4 has been replaced by D-Pro (peptide I), L-thiazolidine-4-carbox- ylic acid (Thz) (peptide II), and dehydro Pro (APro) (peptide III) (fig. 1). The insulinotropic action of CCK-4 and its synthetic congeners (I, II and III) have been studied at stimulatory and non-stimulatory concentrations of glucose on the islets of Langerhans. MATERIALS AND METHODS Animals - Charles Foster albino (male) rats (100-150 g) obtained from the animal colony of the Central Drug Research Institute, Lucknow, were maintained on a Hindustan Lever Pellet dieL Drugs - CCK-4was synthesized by the procedure reported earlier 1. The synthetic congeners I, II and III were obtained by condensation of the C-terminal fragment Asp-Phe-NH 2 with the Key-words: CCK-4 analogues; Glucagon secretion; Insulin secretion. C.D.R.I. Communication n ~ 4735. Abbreviations for amino acids and peptide derivatives according to IUPAC-IUB Commission on Biochemical Nomenclature [Biochemistry (Wash.) 11, 1726, 1972]. Received: September 6, 1990. Acta diabetol, fat. 28, 19-27, 1991. 19