We examined the roles of cholecystokinin (CCK)-2 receptors in the regulation of pepsinogen secretion in the CCK-1 receptor deficient Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Pepsinogen secretion was determined in fasted acute fistula OLETF and control Long-Evans Tokusima Otsuka (LETO) rats. Pepsinogen secretion in OLETF rats under basal conditions as well as in response to CCK-8 stimulation was significantly higher than that in LETO rats. CCK-1 receptor specific agonist ARL 15849 was unable to stimulate pepsinogen secretion in OLETF rats, whereas it elicited pepsinogen secretion in LETO rats to levels similar to those obtained with equimolar CCK-8 stimulation. CCK-2 receptor antagonist reduced basal pepsinogen secretion and completely abolished CCK-8-stimulated pepsinogen output in OLETF rats, whereas in LETO rats, it reduced basal pepsinogen secretion but augmented CCK-8-stimulated pepsinogen output. CCK-1 receptor antagonist loxiglumide also greatly decreased CCK-8-stimulated pepsinogen secretion in OLETF rat, which indicates that loxiglumide is not a specific CCK-1 receptor antagonist. Intravenous infusion of somatostatin antagonist significantly increased CCK-8-stimulated pepsinogen secretion in LETO rats, whereas it had no significant influence on CCK-8-stimulated pepsinogen secretion in OLETF rats. These results indicate that CCK-8 stimulates pepsinogen secretion via CCK-2 receptors in CCK-1 receptor deficient OLETF rats and that the higher CCK-8-stimulated as well as basal pepsinogen secretion in OLETF rats might result from an elimination of tonic inhibition by somatostatin that is released from D cells through mainly CCK-1 receptors.

01 Jun 2000·Journal of medicinal chemistryQ1 · MEDICINE

CCK Peptides with Combined Features of Hexa- and Tetrapeptide CCK-A Agonists

Q1 · MEDICINE

Article

Author: Kaiser, Frederick ; Comstock, Jeanne M. ; Rosamond, James D. ; Julien, Ronald ; Simmons, Roy D. ; Pierson, M. Edward

Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of tetrapeptides, and most recently a series of benzodiazepines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(SO(3)H) and Tac groups may not interact at the CCK-A receptor in the same location. However, the C-terminal dipeptide part of the hexapeptides and tetrapeptides appear to interact at the CCK-A receptor in a similar manner. Compound 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH(2)) derived from combining the features of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered intraperitoneally produces potent, long-lasting reduction in food intake in rats and a corresponding weight loss when administered over nine consecutive days.

01 Mar 1999·Pharmacology, biochemistry, and behaviorQ4 · PSYCHOLOGY

Behavioral Effects of AR-R 15849, a Highly Selective CCK-A Agonist

Q4 · PSYCHOLOGY

Article

Author: F.C Kaiser ; T.J Hudzik ; R.D Simmons

The behavioral effects of AR-R 15849, a novel cholecystokinin agonist with high affinity and selectivity for the CCK-A receptor subtype, were examined. Initially, using an operant feeding paradigm to test for anorectic activity and specificity, acute administration of AR-R 15849 was found to alter the intake and pattern of feeding in a manner similar to prefeeding. Further, AR-R 15849 did not induce compensatory feeding as did CCK-8, and did not affect performance on running rates of responding, or motor activity on a running wheel, as did fenfluramine. In tests for subchronic anorectic activity, daily intraperitoneal injections of AR-R 15849 significantly reduced food intake in fasted rats over a 9-day test period with greater efficacy compared to its nonselective predecessor AR-R 14294 (formerly FPL 14294). The sustained decrease in food intake with AR-R 15849 treatment resulted in a significant reduction in body weight gain over 9 days. Finally, an experiment designed to determine the effect of caloric deprivation and subchronic drug exposure on the overall efficacy of AR-R 15849 indicated that pharmacological tolerance does not develop following subchronic treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	United Kingdom	Astra Arcus AB	-

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