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 alpha(2)-adrenoceptor

7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are pot ent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28 ), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, m ost of these compounds also exhibit strong affinity for the aa-adrenoceptor . To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibito ry activity and alpha(2)-adrenoceptor affinity were investigated by evaluat ing a number of 7-substituted-THIQs. A classical quantitative structure-act ivity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenocep tor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and li pophilicity play a similar role at either active site but that electronic e ffects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substi tuents would not occupy the same region of space at either binding site. Us ing these two binding orientations, based on the lipophilicity of the 7-sub stituent, comparative molecular field analysis (CoMFA) models were develope d 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 alpha(2)-adrenoceptor and that the elec trostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQ s bearing a nonlipophilic electron-withdrawing group at the 7-position, The se QSAR and CoMFA results will be useful in the design of potent and select ive (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.