SBIR-STTR Award

Alpha adrenoceptors serve numerous functions throughout the peripheral and central nervous systems. Chemical modulators of these receptors have a variety of potential therapeutic applications, including treatments for benign prostatic hyperplasia, hypertension, pain and glaucoma. Although six alpha adrenoceptor subtypes are now known, little information is available concerning the locations and physiological functions of these subtypes in the body. The three-dimensional structures of these receptors, and the chemical nature of their interactions with ligands are also poorly understood. Ligands were identified by our cloned human receptor screening program which bind selectively to individual alpha adrenoceptor subtypes. In Phase 1, some of these compounds will be used as templates for the design of new pharmacological tools. These tools will include molecules that selectively inactivate one subtype by covalent modification, as well as subtype-selective radioligands. In Phase I and II, these new pharmacological tools will be used to determine the localization and functional capabilities of the different alpha adrenergic subtypes in various human and animal tissues. These tools will also be useful for structural characterizationof the receptor-ligand complexes. Information obtained in these studies will aid the identification of new therapeutic opportunities and the design of new drugs.Awardee's statement of the potential commercial applications of the research:Identification of the anatomical locations and physiological roles of individual adrempceptor subtypes will increase our understanding of which subtypes to target in order to achieve a particular therapeutic result, and which subtypes to avoid in order to minimize side-effects. Drug development objectives include I antagonists for benign prostatic hyperplasia which do not cause orthostatic hypotension, and non-sedating a2 agonists for analgesia.National Institute of Neurological Disorders and Stroke (NINDS)

Alpha 1 and alpha 2 adrenergic receptors serve numerous functions throughout the central and peripheral nervous systems and, as such, have served as useful targets for the development of drugs to treat of a number of disorders such as narcolepsy, intractable pain, hypertension, benign prostatic hyperplasia and glaucoma. Unfortunately, many alpha adrenergic drugs that have been developed have had significant side-effects which have limited their therapeutic usefulness. The recent identification of six alpha adrenergic receptor subtypes (alpha1a, alpha1b, alpha1d, alpha2a, alpha2b, alpha2c) may allow for the discovery of improved therapeutic alpha adrenergic agents with improved efficacy and fewer side-effects. The proposed research involves the design and synthesis of subtype- selective alpha adrenergic irreversible ligands, photoaffinity ligands and radioligands. These tool compounds will be characterized using cloned human, rat and dog alpha adrenergic receptors and used to study the distribution and functional relevance of alpha 1 and alpha 2 subtypes in intact tissues. In addition, these tool ligands will also be used in structure-function studies using mutated and chimeric receptors to study ligand-receptor interactions. These studies should provide valuable information which will aid the discovery of novel subtype-selective adrenergic drugs. PROPOSED COMMERCIAL APPLICATION: This research will lead to the development of novel, subtype-selective drugs which target alpha adrenergic receptors and may be useful for the treatment of diseases such as narcolepsy, intractable pain, hypertension, begin prostatic hyperplasia, urinary incontinence and glaucoma with fewer side-effects than existing therapeutic agents.

Thesaurus Terms:
alpha adrenergic receptor, drug design /synthesis /production, receptor binding affinity labeling, autoradiography, radiotracer