E. Smissman, J. Reid, D. A. Walsh
1976
Citations
1
Influential Citations
24
Citations
Quality indicators
Journal
Journal of medicinal chemistry
Abstract
Various 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisquinolines were synthesized and evaluated as substrates and inhibitors of catechol O-methyltransferase (COMT). In addition, these compounds were tested for their ability to release norepinephrine-3H from mouse hearts in vivo. Methyl substituents in the 2 and/or 4 positions of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline had little effect on the interaction of these molecules with COMT. In general, the substrate kinetic (Km, Vmax) and inhibitory kinetic (Kis) properties toward COMT were similar for each of these compounds. In contrast, norepinephrine depleting activity showed more strict structural requirements. Methyl substituents in the 2 or 4 positions of the parent compound, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, eliminated the norepinephrine depleting activity. The interesting exception was 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was found to be more active than the parent molecule as a depleter of norepinephrine from mouse hearts.