Synthesis and Biochemical Evaluation of 3-Fluoromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-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.

Nickel‐Catalyzed Reductive Cross‐Coupling of Aryl Halides with Monofluoroalkyl Halides for Late‐Stage Monofluoroalkylation

“…As the monofluoro- 1b py (10) DMAc 17 2d mbpy (10) DMAc 21 3d tbpy (10) DMAc 17 4d ombpy (10 [c] dmbpy (10) [c,d] dmbpy (10) methyl group (CFH 2 )iswidely used as akey motif to improve the biological properties of candidate drug molecules, [12] this method provides an ew strategy for the facile synthesis of monofluoromethylated arenes to meet the demands of drug screening. Not surprisingly,the length of the alkyl chain in 2 had no evident influence on the reaction efficiency (products 35-37).…”

Exploring the active site of phenylethanolamine N-methyltransferase with 3-hydroxyethyl- and 3-hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoquinolines

“…A compound possessing a calculated log P 11,12 value greater than 0.5 is likely required for 1,2,3,4-tetrahydroisoquinoline-type (THIQ-type) PNMT inhibitors to achieve significant CNS penetration. 13 A potent inhibitor of PNMT that is both selective and capable of crossing the blood-brain barrier (BBB) would be a useful pharmacological tool to help define the role of CNS Epi.…”

Inhibitors of phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity

“…Hydrogenation of 9 gave aniline 10, which was converted to iodo-lactam 11 via a Sandmeyer iodination. 15 Reduction of 11 with BH 3 AETHF gave 5b. Treatment of 11 with FSO 2 CF 2-CO 2 CH 3 and CuI in DMF gave the trifluoromethyl analogue (12), which was reduced to 5c.…”

“…[7][8][9][10][11][12][13] However, most of these inhibitors either display significant affinity for the a 2 -adrenoceptor (e.g., 1,2), 10,14 which complicates the interpretation of their biological effects, or those inhibitors that are selective for PNMT are too polar to pass the blood-brain barrier (BBB) (e.g., 3,4). 8,12,15 In light of these limitations, there remains an ongoing interest in the development of a PNMT inhibitor that is both sufficiently lipophilic to penetrate the BBB and is devoid of affinity for the a 2 -adrenoceptor.…”

“…Treatment of lactam 8 with chlorosulfonic acid (neat) gave 14, which was reacted with ethylamine or ammonium hydroxide to give 15a or 15b, followed by reduction with BH 3 AETHF to give 5h or 5j. 15 The enantiomers of 5b, 5c, 5e, and 5f were separated by chiral HPLC. 19 The absolute configurations of 5c and 5e were established by the X-ray structure analysis of (R)-5cAEHCl and (R)-5eAEHCl.…”