Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

Abstract

7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the alpha2-adrenoceptor. To design a selective (PNMT vs alpha2-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha2-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pKi = 0.599pi - 0.0725MR + 1. 55sigmam + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha2-adrenoceptor (alpha2 pKi = 0.599pi - 0. 0542MR - 0.951sigmam + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha2-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position. These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha2-adrenoceptor affinity) inhibitors of PNMT.

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

“…The organic layer was removed and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure to yield the crude product as a yellow solid, which was purified by flash chromatography eluting with hexanes/ether/CH 2 00 (s, 3H), 3.97 (s, 3H), 3.30-3.20 (m, 1H, major and minor rot. ) N-Nvoc-4-chloro-6-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde [(S)-47] and (S)-N-Nvoc-4-chloro-2-methyl-1,2,5,6-tetrahydropyridine-3 General Procedure for Nvoc Deprotection-(Selected procedure for (R)-30·HCl).…”

“…Brine (50 mL) was added and the aqueous mixture was extracted with CH 2 Cl 2 (3 × 50 mL). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na 2 6 mmol), and DCE (100 mL) were reacted in a thick-walled pyrex bottle sealed with a Teflon screw cap at 100 °C for 72 h. The reaction was cooled and filtered through Celite, which was washed with CH 2 Cl 2 (3 × 50 mL). The solvent was removed under reduced pressure to yield oxazine 54.…”

“…However, THIQs bearing lipophilic 7-substituents are less selective than THIQs bearing hydrophilic 7-substituents due to significant affinity for the α 2 -adrenoceptor. 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.…”

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

“…THIQs having electron-withdrawing 7-substituents (either lipophilic or hydrophilic) are highly potent inhibitors of PNMT, 21 and those with lipophilic electron-withdrawing 7-substituents, such as halides (7 and 8) are generally more potent than those having hydrophilic groups [9 and SK&F 29661 22 (10)]. Unfortunately, THIQs bearing lipophilic electron-withdrawing 7-substituents also have significant affinity for the α 2 -adrenoceptor.…”

Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors☆

“…13 Similarly, THBQs having hydrophilic electron-withdrawing 7-substituents (14, 15, and 18) have less affinity for the α 2 -adrenoceptor than 11. For the nitro, cyano, and aminosulfonyl THIQ and THBQ derivatives, the relative α 2 -adrenoceptor affinity versus the parent compounds is very similar.…”