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

Abstract

A tetrahydroisoquinoline identified in Mucuna pruriens ((1R,3S)-6,7dihydroxy-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-Omethyltransferase (COMT) with no affinity for the dopaminergic receptors or the dopamine transporter. It restores dopamine-mediated motor behavior when it is coadministered with L-DOPA to C. elegans worms with 1-methyl-4-phenylpyridiniumdamaged 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.

The Pesticide Chlordecone Promotes Parkinsonism-like Neurodegeneration with Tau Lesions in Midbrain Cultures and C. elegans Worms

“…For subsequent neurotoxicity experiments, a concentration of 15 µM of CLD inducing a mortality rate of approximately 40%, was most commonly used. In comparison, a concentration of 1 mM of MPP + used to model DA cell loss in C. elegans worms [50] produced a mortality rate of 60% under the present conditions. Note that quantitative data for subsequent neurotoxicity studies were obtained in the worms that remained alive and well-formed after exposure to CLD.…”

4-phenylbutyric acid improves sepsis-induced cardiac dysfunction by modulating amino acid metabolism and lipid metabolism via Comt/Ptgs2/Ppara

“…It was found to be closely relate to the development and medication of many types of diseases such as psychiatric and neurological, oncological and cardiovascular diseases, and was an important drug target (Hall et al, 2019 ). Currently, COMT inhibitors are used in clinical practice in combination with levodopa for the treatment of Parkinson’s disease (Parrales-Macias et al, 2022 ). In our study, we found that PBA could target Comt and exert cardioprotective effects by inhibiting its expression in sepsis.…”

Diastereoselective Synthesis of (–)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid via Morpholinone Derivatives

“…THIQs containing natural and synthetic molecules have been qualified as ‘privileged scaffolds’ to identify, design, and synthesize novel biologically active derivatives of interest in drug development, from anti-inflammatory, anti-viral, anti-fungal, or anti-cancer compounds to Parkinson’s disease treatment [ 4 , 5 , 6 , 7 ]. 1,2,3,4-Tetrahydroisoquinoline carboxylic acids in their optically pure form are important building blocks for the synthesis of natural products and synthetic pharmaceuticals, and are currently subject to growing interest [ 8 , 9 , 10 , 11 , 12 ]. Recently, a series of optically active substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives ( A ) ( Figure 1 ) such as esters and amides have been synthesized and evaluated as potent influenza virus polymeraze acidic (PA) endonuclease domain inhibitors [ 10 ].…”

“…6,7-Dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid ( B ) ( Figure 1 ), isolated from Mucuna pruriens, traditionally used for the treatment of Parkinson’s disease, and synthetized from L-DOPA, behaves as a peripheral catechol- O -methyltransferase inhibitor (COMTI). Therefore, it may be a promising drug candidate for the development of COMT inhibitors useful in the treatment of Parkinson’s disease [ 11 ]. 1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid ( C ) ( Figure 1 ) can efficiently inhibit in vitro the activity of NDM-1 (New Delhi metallo-β-lactamase), which is widespread in many bacteria and is able to hydrolyze almost all β-lactam antibiotics [ 12 ].…”