Novel CCK Analogs for Studying CCK‐B Receptor

Cholecystokinin (CCK) is a typical brain-gut peptide that localizes not only in the endocrine system but also in the central and peripheral nervous systems and that exhibits various biological activities in different mammalian tissues and organs. Although tissue forms of CCK-related peptides have been identified and sequenced, it has still not been established which forms are released into blood as proper hormone and/or transmitter. CCK-8 possesses the full biological properties of CCK, and structure-activity studies of CCK, which have been carried out in several laboratories worldwide, have been devoted mainly to CCK-8 or CCK-7. In an earlier study,' we demonstrated dissociation of pancreatic exocrinestimulating (PZ) activity from gallbladder-contracting (CCK) activity in Nasuccinylated [D-Trp3]-CCK-7 (Suc-[D-Trp3]-CCK-7) in anesthetized dogs. Several other synthetic analogs of CCK-7 and CCK-8, in which the Gly residue was substituted, as well as the [D-Trp3] analog were also shown to possess full or almost full PZ activities in anesthetized rats as compared with CCK-8, whereas they were considerably less potent in CCK activity in anesthetized guinea pigs. These observations suggested the possible existence of multi-subtypes of CCK receptor in the gut. We then proposed the usefulness of synthetic analogs of CCK-7 and CCK-8 as tools for distinguishing between receptors associated with CCK and PZ activities. Subsequently, we succeeded in differentiating CCK binding properties of rat pancreatic and brain receptors with the use of various synthetic CCK COOH-terminal-related peptides and analogs.* Our results, together with recent progress in research on CCK receptors in other laboratories, encouraged us to extend our study on characterization of CCK receptors in various tissues specifically with the use of synthetic CCK