DESCRIPTION: We propose to characterize conantokins for the treatment of Parkinson's disease. Conantokins are small peptides originally isolated from cone snail venom which antagonize a subset of NMDA receptors through a unique mechanism. Since NMDA antagonists have been proposed for the treatment of Parkinson's disease, we have explored the antiparkinsonian potential of conantokins. Preliminary data show that Conantokin-G potentiates rotation induced by L-dopa in rats with unilateral 6-hydroxy-dopamine-induced dopamine lesions, an animal model of Parkinson's disease. These data suggest that conantokins, which may lack the side effects common to other NMDA antagonists, may represent a novel treatment for Parkinson's disease. In phase 1, we will: (1) establish the efficacy of icv conantokins to induce contralateral rotation or potentate rotation induced by dopamine agonists in this model , (2) assess expression of the immediate early genes c-fos and zif268 in selected basal ganglia nuclei in which conantokins act. In phase 2 we propose to; (1) characterize conantokins and analogs (designed for improved bio-availability) in additional animal models; (2) assess efficacy of conantokins following various routes of peripheral administration; and (3) examine the effects of conantokins on neurodegeneration of dopamine neurons in vivo. PROPOSED COMMERCIAL APPLICATION: Parkinson's disease, which afflicts more than half a million Americans, is characterized by a loss of striatal dopamine. Treating Parkinson's disease involves restoring dopamine with L-Dopa. Since significant side effects limit L-Dopa use there is a clear need for alternatives. Conantokins, novel, subtype-selective NMDA antagonists (which may lack typical NMDA antagonist associated toxicities), are effective in an animal model of Parkinson's disease, and may represent a novel therapy for Parkinson's disease. Thus, conantokins have tremendous potential as commercial drugs for Parkinson's patients.