title: Synthesis and biochemical evaluation of 3-fluoromethyl-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.
abstract: A series of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines (3-fluoromethyl-THIQs) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of comparative molecular field analysis (CoMFA) models. These compounds were synthesized and evaluated for affinity at PNMT and the alpha(2)-adrenoceptor. It was discovered that these compounds are some of the most selective inhibitors of PNMT versus the alpha(2)-adrenoceptor known. To determine the ability of these compounds to penetrate the blood-brain barrier (BBB), a series of THIQs possessing a variety of calculated partition coefficients (Clog P) were assayed using an in vitro BBB model. This study found a good correlation between lipophilicity (Clog P) and BBB permeability, which indicated that THIQs possessing Clog P values of at least 0.13-0.57 should have some penetration into the brain. Two compounds [3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (18) and 3-fluoromethyl-7-cyano-THIQ (20)] possess calculated partition coefficients greater than 0.57 and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200 and thus represent promising leads in the development of highly selective inhibitors of PNMT with the ability to penetrate the BBB.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ukans.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: T M
authors.initials: TM
authors.lastname: Caldwell
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Slavica
authors.forename: K R
authors.initials: KR
authors.lastname: Criscione
authors.forename: R T
authors.initials: RT
authors.lastname: Borchardt
authors.forename: W
authors.initials: W
authors.lastname: Wang
mesh_terms: D000311:Adrenal Glands / Q000201:enzymology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D002417:Cattle; D003000:Clonidine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D010539:Permeability; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D004791:Enzyme Inhibitors; D017611:Fluorine Compounds; D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine