1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase.
In order to determine the function of epinephrine (Epi) in the central nervous system, we have targeted the enzyme that catalyzes the final step in the biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). 1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzyme, but also display affinity for the alpha2-adrenoceptor. To gain further understanding about how THIQs bind at the PNMT active site and in an attempt to further increase the selectivity of THIQ-type inhibitors versus the alpha2-adrenoceptor, a series of cis- and trans-1,3-dimethyl-7-substituted-THIQs were synthesized. Evaluation of these compounds suggests that THIQs bind in two different orientations at the PNMT active site, based on the lipophilicity of the 7-substituent. However, no significant increases in selectivity versus the alpha2-adrenoceptor were observed for these compounds.
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA. ggrunewald@ukans.edu
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D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011941:Receptors, Adrenergic / Q000378:metabolism; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011941:Receptors, Adrenergic; D010625:Phenylethanolamine N-Methyltransferase