New Pharmacological Tools for Alpha Adrenergic Receptors

Alpha adrenoceptors serve numerous functions throughout the peripheral and central nervoussystems. Chemical modulators of these receptors have a variety of potential therapeutic applications,including treatments for benign prostatic hyperplasia, hypertension, pain and glaucoma. Although sixalpha adrenoceptor subtypes are now known, little information is available concerning the locations andphysiological functions of these subtypes in the body. The three-dimensional structures of thesereceptors, and the chemical nature of their interactions with ligands are also poorly understood. Ligandswere identified by our cloned human receptor screening program which bind selectively to individualalpha adrenoceptor subtypes. In Phase I, some of these compounds will be used as templates for thedesign of new pharmacological tools. These tools will include molecules that selectively inactivate onesubtype by covalent modification, as well as subtype-selective radioligands. In Phase I and II, these newpharmacological tools will be used to determine the localization and functional capabilities of the differentalpha adrenergic subtypes in various human and animal tissues. These tools will also be useful forstructural characterization of the receptor-ligand complexes. Information obtained in these studies willaid the identification of new therapeutic opportunities and the design of new drugs.