Structure-function relationships of new synthetic CCK/sub 8/ analogs in rat brain and pancreas

Cholecystokinin (CCK) receptors are found in the pancreas, brain, and other tissues. The purpose of the present study was to develop new carboxy-terminal analogs of CCK/sub 8/ to be used as probes for studying CCK receptor heterogeneity. Four analogs of (Nle/sup 28,31)-CCK/sub 26-33/ were therefore prepared. These compounds were evaluated in competition-inhibition studies in rat cortical and pancreatic membranes, using (/sup 3/H)-propionyl-CCK/sub 8/ as the radiolabeled ligand. The N-terminal sulfonamide and N-acetyl derivatives were 3-fold less potent than CCK/sub 8/ in inhibiting pancreatic binding but were equipotent with CCK/sub 8/ in inhibiting cortical binding. The potency of the D-Phe/sup 33/ and L-Leu/sup 33/ N-terminal sulfonamide analogs was greatly reduced in both tissues. All 4 analogs exerted characteristically biphasic effects on amylase release from pancreatic acini, but the potency of D-Phe/sup 33/ and L-Leu/sup 33/ was greatly reduced. The presence of D-Phe or L-Leu in position 33 markedly reduced binding and biological activity of (Nle/sup 28,31/)-CCK/sub 26-33/, whereas the addition of a sulfonamide at its amino-terminal end did not significantly alter either binding or biological activity. These findings suggest that sulfonamide analogs of CCK/sub 8/ may be useful for studying the CCK receptor.