Research Project
3504188
Evidence suggests receptors mediating CNS responses to gamma- aminobutyric acid (GABA) are heterogeneous and the designations of GABA/A and GABA/B have been advanced to differentiate major receptor subtypes. GAVA/a receptors are 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 antagonist are available to evalutae GABA/A receptors function. However, baclofen (BAC) is the only selective agonist for GABA receptors and no potent and specific antagonists have been identified. Biochemical and physiological evidence indicate GABA/A receptor mediate classical synaptic neurotransmission wheras GABA/B receptors may be involved in modulation of neuronal activity. Thus, GABA may function in a dual capacity as a neurontransmitter and neuromodulator in brain. BAC represents a widely used antispastic agent. However, deleterious side-effects attending BAC administration are documented. Heterogenety among GABA/B receptors suggests the possibility of developing more selective GABA/B agonists of therapeutic potential. Furthermore, reason exists to beleive that GABA/B antagonists could be of therapeutic utility, for instance, in the reatment of Parkinson Disease or as CNS stimulants. Because such compounds would modulate rather than mimick (inhibit) neutrotransmission, GABA/B receptor agonists and antagonists would represent a subtle approach to influence GABA- mediaed events in brain. The Phase I proposal seeks support to develop a program to identify GABA/B receptor agonists and antagonist. Methods will 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 indentified as having the desired pharmacological properties will provide lead structures to initiate synthetic chemical efforts in the Phase II portion of the application.
