Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor

Abstract

An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

“…The docking of inhibitors into the hPNMT active site was performed on the R-enantiomer as a previous study on 3-substituted-THIQs indicated that the R-enantiomer is preferred over the S-enantiomer in the hPNMT active site. 60 Difluoroacetonitrile (29) was prepared according to a procedure reported by Swarts. 31 Difluoroacetamide (28, 2.30g, 24.2 mmol) and P 2 O 5 (5.00 g, 17.6 mmol) were stirred to a homogeneous mixture in a 50 mL RB flask equipped with a short path distillation head.…”

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

“…2 The addition of small substituents (e.g., methyl, 10) to the 3-position of THIQ increases potency at hPNMT while decreasing affinity for the α 2 -adrenoceptor. 3,4 The absolute stereochemistry at the 3-position of THIQs is important and is discussed below. A synergistic effect is achieved by adding both 3-and 7-substituents to THIQ, resulting in multiplicative increases in PNMT inhibitory potency and selectivity versus the α 2 -adrenoceptor compared to the similarly substituted 3-or 7-monosubstituted THIQs.…”

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

“…15 The docking of inhibitors into the hPNMT active site was performed on the R-enantiomer as a previous study on 3-hydroxymethyl-7-substituted-THIQs indicated that the R-enantiomer is preferred over the S-in the hPNMT active site. 32 Residues Lys57 and Met258 move within the PNMT active site depending on the hydrophobicity of the 7-substitutent. 15 Inhibitors that contain a 7-nitro substituent were docked into the crystal structure of hPNMT co-crystallized with SK&F 29661 (4), 16 whereas inhibitors that possess a 7-bromo substituent were docked into the crystal structure of hPNMT cocrystallized with 7-iodo-THIQ (3).…”