Synthesis and biochemical evaluation of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor

A series of 3-nuoromethyl-1,2,3,4-tetrahydroisoquines (3-fluoromethyl-THIQs ) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of compara tive molecular field analysis (CoMFA) models. These compounds were synthesi zed and evaluated for affinity at PNMT and the alpha(2)-adrenoceptor. It wa s discovered that these compounds are some of the most selective inhibitors of PNMT versus the az-adrenoceptor known. To determine the ability of thes e compounds to penetrate the blood-brain barrier (BBB), a series of THIQs p ossessing a variety of calculated partition coefficients (Clog P) were assa yed using an in vitro BBB model. This study found a good correlation betwee n lipophilicity (Clog P) and BBB permeability, which indicated that THIQs p ossessing 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)amino (18 ) and 3-fluoromethyl-7-cyano-THIQ (20)] possess calculated partition coeffi cients greater than 0.57 and display selectivities (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 BB B.