Activation of a subset of serotonin receptors evokes physiological responses characteristic of adenylate cyclase stimulation in a wide variety of tissues: neuronal depolarization, relaxation of smooth muscle, and positive inotropy in cardiac muscle. The receptor subtypes will serve as drug targets for potential therapeutic roles in irritable bowel disease, postoperative ileus, diabetic gastroparesis, emesis, achalasia, hiatal hernia, esophageal spasm, angina, coronary artery disease, atherosclerosis, stroke, and disorders of higher cognitive processes. Despite the obvious medical significance of this subfamily of serotonin receptors which couple to the to the activation of adenylate cyclase, the molecular characterization of the family of serotonin receptors coupled to activation of adenylate cyclase has not been well documented. Phase I of this proposal will attempt to identify members of this family and to characterize the tissue distribution of these receptors. Such information should provide valuable data on the physiological responses to serotonin activation which are coupled to increase in cAMP. In Phase II, we shall initiate a drug development program which focuses on designing receptor-specific compounds.
