EXAMINATION OF THE ROLE OF THE ACIDIC HYDROGEN IN IMPARTING SELECTIVITY OF 7-(AMINOSULFONYL)-1,2,3,4-TETRAHYDROISOQUINOLINE (SK-AND-F-29661) TOWARD INHIBITION OF PHENYLETHANOLAMINE N-METHYLTRANSFERASE VS THE ALPHA(2)-ADRENOCEPTOR

7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), In contrast to other inhibitors of PNMT, it is al so highly selective toward PNMT in comparison with its affinity toward the alpha(2)-adrenoceptor (PNMT K-i = 0.55 mu M, alpha(2) K-i = 100 m u M, selectivity [alpha(2) K-i/PNMT K-i] = 180). A diverse set of comp ounds was synthesized and evaluated to probe the role of the acidic hy drogen of the aminosulfonyl group of 1 in imparting this selectivity. Compounds were designed to investigate the effect on selectivity of th e acidity of the NH group [the 7-N-methyl (compound 5) and 7-N-(p-chlo rophenyl) (compound 4) derivatives of 1], the relative spatial positio n of the acidic hydrogen thylsulfonyl)amino)-1,2,3,4-tetrahydroisoquin oline (6) and fonyl)amino)methyl)-1,2,3,4-tetrahydroisoquinoline (8)], or the effect of the substitution of an acidic phenolic group for the aminosulfonyl moiety [1-(aminomethyl)-6-hydroxynaphthalene (23) and 8 -hydroxy-1,2,3,4-tetrahydrobenz[h]isoquinoline (9)]. All of the compou nds studied displayed lower affinity for PNMT than I, and nine of the eleven compounds studied showed increased, rather than the desired dec reased, affinity for the alpha(2)-adrenoceptor. Specifically, compound 4, in which the aminosulfonyl NH group is more acidic than that in 1, showed greatly reduced selectivity on account of increased alpha(2)-a drenoceptor affinity as compared to 1 (PNMT K-i = 2.6 mu M, alpha(2) K -i = 6.3 mu M, selectivity = 2.4). Compound 8, in which the acidic NH group is in the same region of space as that in 1, although the aminos ulfonyl group is reversed with respect to the aromatic ring, showed po or PNMT affinity and modest alpha(2)-adrenoceptor affinity (PNMT K-i = 330 mu M, alpha(2) K-i = 18 mu M, selectivity = 0.055). Compound 9, i n which a phenolic group is in the same region of space as the acidic NH of 1, exhibited the best alpha(2)-adrenoceptor affinity of any of t he compounds studied (PNMT K-i = 0.98 mu M, alpha(2) K-i = 0.078 mu M, selectivity = 0.080). Results from this study suggest that the select ivity of 1 is not solely due to the presence of an acidic hydrogen on the 7-aminosulfonyl group of 1 but is likely also dependent on some ot her property (e.g.electron-withdrawing character) of the aminosulfonyl group.