Journal
ACS CHEMICAL NEUROSCIENCE
Volume 13, Issue 23, Pages 3303-3313Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00356
Keywords
Parkinson?s disease; catechol-O-methyltransferase; Mucuna pruriens; Caenorhabditis elegans; dopaminergic pathway; animal models
Funding
- Labex Lermit [ANR-10-LABX-33]
- Ministry of Higher Education of Syria [1034]
- France Parkinson
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A tetrahydroisoquinoline compound identified in Mucuna pruriens exhibits promising effects in Parkinson's disease animal models by inhibiting COMT and restoring dopamine-mediated motor behavior.
A tetrahydroisoquinoline identified in Mucuna pruriens ((1R,3S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid, compound 4) was synthesized and assessed for its in vitro pharmacological profile and in vivo effects in two animal models of Parkinson's disease. Compound 4 inhibits catechol-O- 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 C. elegans 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 1 at 30 mg/kg but for a shorter duration. The effect is not dose-dependent. Compound 4 seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound 4 further validates the traditional use of M . pruriens for the treatment of Parkinson's disease, and compound 4 can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.
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