DRUG DESIGN FOR THE TREATMENT OF BLADDER INCONTINENCE

MUSCARINIC ACETYLCHOLINE RECEPTORS ARE THE PRIMARY MEDIATORS OF CHOLINERGIC NERVOUS INPUTS CONTROLLED BY THE PARASYMPATHETIC NERVOUS SYSTEM. STRUCTURAL HETEROGENEITY IN THIS RECEPTOR FAMILY HAS BEEN LONG SUSPECTED ON THE BASISOF THE BINDING CHARACTERISTICS OF VARIOUS TISSUES TO A VARIETY OF LIGANDS. THE RECENT CLONING OF MEMBERS OF THIS RECEPTOR FAMILY HAS PROVEN THAT AT LEAST FIVE DISTINCT LOCI ARE PRESENT WITHIN THE GENOME WITH EACH RECEPTOR SUBTYPE DISPLAYING AN INDIVIDUAL PATTERN OF LOCALIZATION WITHIN SELECTED TISSUES. THIS PROJECT SEEKS TO ESTABLISH A MORE COMPLETE PICTURE OF THE PHYSICAL LOCALIZATION OF THE VARIOUS MUSCARINIC RECEPTORSUBTYPES WITHIN THE AUTONOMIC NERVOUS TISSUE. THIS WILL BE CORRELATED WITH ANALYSIS OF THE FUNCTIONAL PROPERTIES OF THERECEPTORS IN EACH TISSUE TO PROVIDE A PICTURE OF THE METABOLIC RESPONSES ACTIVATED WITHIN VARIOUS ORGANS BY CHOLINERGIC INNERVATION. THE RESEARCH WILL CONCENTRATE ON ANALYSIS OF THE URINARY BLADDER, AN ORGAN WHOSE CONTRACTILE FUNCTION IS ALMOST COMPLETELY CONTROLLED BY MUSCARINIC RECEPTORS. BLADDER INCONTINENCE IS KNOWN TO BE A FUNCTIONAL DISORDER WITH GROWING CONSEQUENCES FOR THE AGING POPULATION. NEUREX CORPORATION INTENDS TO DEVELOP A MORE RATIONAL APPROACH TO THE DEVELOPMENT OF A THERAPY FOR THE TREATMENT OF THIS DISORDER THROUGH AN IMPROVED UNDERSTANDING OF THE UNDERLYINGPHARMACOLOGICAL BASIS FOR DYSFUNCTION AT THE LEVEL OF THE REGULATORY RECEPTORS.