Effects of a New Natural Catechol--methyl Transferase Inhibitor on Two In Vivo Models of Parkinson's Disease.

A tetrahydroisoquinoline identified in ((1,3)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid, compound ) was synthesized and assessed for its pharmacological profile and effects in two animal models of Parkinson's disease. Compound inhibits catechol--methyltransferase (COMT) with no affinity for the dopaminergic receptors or the dopamine transporter. It restores dopamine-mediated motor behavior when it is co-administered with L-DOPA to worms with 1-methyl-4-phenylpyridinium-damaged dopaminergic neurons. In a 6-hydroxydopamine rat model of Parkinson's disease, its co-administration at 30 mg/kg with L-DOPA enhances the effect of L-DOPA with an intensity similar to that of tolcapone at 30 mg/kg but for a shorter duration. The effect is not dose-dependent. Compound seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound further validates the traditional use of for the treatment of Parkinson's disease, and compound can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.