GABA(B) RECEPTOR AGONISTS AND ANTAGONISTS

EVIDENCE SUGGESTS RECEPTORS MEDIATING CNS RESPONSES TO -AMINOBUTYRIC ACID (GABA) ARE HETEROGENEOUS AND THE DESIGNATIONS OF GABA(A) AND GABA(B) HAVE BEEN ADVANCED TO DIFFERENTIATE MAJOR RECEPTOR SUBTYPES. GABA(A) RECEPTORSARE ANTAGONIZED BY BICUCULLINE (BIC), LINKED TO A PICROTOXIN(PIC)-SENSITIVE CHLORIDE CHANNEL AND, AT LEAST PARTIALLY, ASSOCIATED WITH BENZODIAZEPINE (BZ) RECOGNITION SITES. IN CONTRAST, GABA(B) RECEPTORS ARE INSENSITIVE TO BIC AND PIC, DO NOT APPEAR TO BE FUNCTIONALLY LINKED TO BZ RECOGNITION SITES AND INFLUENCE VOLTAGE-SENSITIVE POTASSIUM AND CALCIUM CURRENTS. MULTIPLE AGONISTS AND ANTAGONISTS AREAVAILABLE TO EVALUATE GABA(A) RECEPTOR FUNCTION. HOWEVER, BACLOFEN (BAC) IS THE ONLY SELECTIVE AGONIST FOR GABA(A) RECEPTORS AND NO POTENT AND SPECIFIC ANTAGONISTS HAVE BEEN IDENTIFIED. BIOCHEMICAL AND PHYSIOLOGICAL EVIDENCE INDICATE GABA(A) RECEPTORS MEDIATE CLASSICAL SYNAPTIC NEUROTRANSMISSION WHEREAS GABA(B) RECEPTORS MAY BE INVOLVED IN MODULATION OF NEURONAL ACTIVITY. THUS, GABA MAY FUNCTIONIN A DUAL CAPACITY AS A NEURONTRANSMITTER AND NEUROMODULATORIN BRAIN. BAC REPRESENTS A WIDELY USED ANTISPASTIC AGENT. HOWEVER, DELETERIOUS SIDE-EFFECTS ATTENDING BAC ADMINISTRATION ARE DOCUMENTED. HETEROGENEITY AMONG GABA(B) RECEPTORS SUGGESTS THE POSSIBILITY OF DEVELOPING MORE SELECTIVE GABA(B) AGONISTS OF THERAPEUTIC POTENTIAL. FURTHERMORE, REASON EXISTS TO BELIEVE THAT GABA(B) ANTAGONISTS COULD BE OF THERAPEUTIC UTILITY, FOR INSTANCE, IN THE TREATMENT OF PARKINSON'S DISEASE OR AS CNS STIMULANTS. BECAUSE SUCH COMPOUNDS WOULD MODULATE RATHER THAN MIMICK (INHIBIT) NEUROTRANSMISSION, GABA(B) RECEPTOR AGONISTS AND ANTAGONISTSWOULD REPRESENT A SUBTLE APPROACH TO INFLUENCE GABA-MEDIATEDEVENTS IN BRAIN. THE PHASE I PROPOSAL SEEKS SUPPORT TO DEVELOP A PROGRAM TO IDENTIFY GABA(B) RECEPTOR AGONISTS AND ANTAGONISTS. METHODSWILL INCLUDE (1) IN VITRO LIGAND BINDING ASSAYS, (2) IN VITRO FUNCTIONAL ASSAYS AND (3) WHOLE ANIMAL TESTING. COMPOUNDS WILL BE SELECTED FROM NOVA'S CURRENT INVENTORY OF CHEMICALS. AGENTS IDENTIFIED AS HAVING THE DESIRED PHARMACOLOGICAL PROPERTIES WILL PROVIDE LEAD STRUCTURES TO INITIATE SYNTHETIC CHEMICAL EFFORTS IN THE PHASE II PORTION OF THE APPLICATION.