Molecular Pharmacology, Vol 15, 287-293, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

2,4-Diamino-5-cyano-6-halopyridines and Analogues. A New Family of Insulin Secretogogues That Resemble Glucose in Hydrogen Bonding Possibilities

¹ Division of Clinical Pharmacology and Division of Metabolism, Endocrinology and Gerontology, Department of Medicine, University of Washington, Seattle, Washington 98195

Rat pancreas was perfused in situ with medium containing 300 mg/dl glucose and 2,4-diamino-5-cyano-6-bromopyndine (Compound I) or several closely related analogues. Addition of 0.1 mM Compound I caused a 3 to 4-fold increase in insulin release. At 1.0 mM concentration Compound I increased insulin release 7 to 20-fold greater than that caused by glucose alone. The augmented release of insulin was biphasic, with a brief initial spike followed by a secondary rise that lasted at least 60 min. Similar results were obtained with 2,4-diamino-5-cyano-6-iodopyridine and 2,4-diamino-3,5-dicyano-6-bromopyridine. Twenty minutes after giving Compound I by gavage to anesthetized rats an intravenous bolus of glucose (0.625 g/kg) was given. During the 60 min interval following glucose, drug-treated animals had almost 3 times higher serum insulin concentrations compared to control animals. The glucose disappearance curves were similar in both groups. These results indicate that Compound I and its analogues are potent insulin secretogogues in vivo and in vitro. The similarity of the hydrogen bonding possibilities of these compounds to glucose suggests that their ability to release insulin may be due to interaction with a glucoreceptor in the pancreatic -cell.

Note:
ACKNOWLEDGMENTS We thank Mrs. Glenda Schneider for excellent technical assistance, Dr. Frederic M. Richards for a sample of Compound I and Dr. V. A. Engelhardt for samples of Compounds III and IV.