10.1021/jm00223a022
The research explore the relationship between the structure of substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (THIQs) and their biological activities, specifically their interactions with catechol O-methyltransferase (COMT) and their ability to release norepinephrine from mouse hearts. The study synthesized various 2- and 4-substituted THIQs and evaluated their substrate and inhibitory kinetic properties towards COMT. It was found that methyl substituents in the 2 and/or 4 positions had little effect on the interaction of these molecules with COMT, as the substrate kinetic (Km, Vmax) and inhibitory kinetic (Ki) properties were similar across the compounds. However, the norepinephrine depleting activity showed stricter structural requirements, with methyl substituents generally eliminating this activity, except for 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was more active than the parent molecule. The key chemicals used included 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, various substituted derivatives thereof, S-adenosyl-L-methionine (SAM) as a methyl donor, and DL-norepinephrine-7-3H for the norepinephrine release assays. The study concluded that minor structural modifications of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline could separate the COMT inhibitory effects from the indirect sympathomimetic effects, suggesting potential for developing new COMT inhibitors with reduced sympathomimetic activity.
