EVIDENCE FOR CHOLECYSTOKININ RECEPTOR SUBTYPE IN ENDOCRINE PANCREAS

Cholecystokinin (CCK) is a gut hormone that regulates pancreatic endoc rine functions via CCKA receptors. CCK4 (Trp-Met-Asp-Phe-NH2) has an i nsulinotropic effect, but is 1000-fold less potent than CCK8. The in v itro potencies and selectivity of newly synthesized CCK analogs were i nvestigated. Exchanging various a amino acids, for example Met by Nle and modifying Phe and/or Trp, led to compounds that were much more eff ective than CCK4 itself and show insulinotropic effects comparable wit h those of CCK8. Compounds that possess electron withdrawing groups on the C-terminal phenylalanine were especially effective; compounds wit h electron-donating groups had no effect. In contrast to CCK8 the synt hetic CCK4 compounds were selective for the endocrine pancreas: they h ad no agonistic or antagonistic effect on the contraction of the guine a pig ileum, amylase release from isolated acini, and no major effect on the feeding behavior of mice being supplied with either compound by an implantable Alzet(R) pump for 8 days. The data indicate that some of the synthetic tetrapeptides exhibit a high affinity for the CCK rec eptor of the endocrine pancreas and that they are highly selective for this (peripheral) CCKA receptor subtype. The beta-cell CCKA receptors are different from those in exocrine pancreas, smooth muscle, and tho se for regulating appetite; these peripheral receptor subtypes can be discriminated for the first time.