THE ORAL ANTIHYPERTENSIVE ACTIVITY OF THE METHYLATED DERIVATIVES OF PHENYL-2-AMINOETHYL SULFIDE

We have reported previously that phenyl-2-aminoethyl sulfide and its d erivatives are excellent substrates for dopamine-beta-monooxygenase an d produce an antihypertensive effect in spontaneously hypertensive rat s after i.p. administration. In the studies reported herein, we demons trate that alpha-methyl-phenyl-2-aminoethyl sulfide and 4-hydroxy-alph a-methyl-phenyl-2-aminoethyl sulfide, the methylated and hydroxymethyl ated derivatives of phenyl-2-aminoethyl sulfide, respectively, decreas e mean arterial pressure in conscious, unrestrained spontaneously hype rtensive rats after p.o. administration. This antihypertensive effect after p.o. administration occurs without the undesirable transient ris e in blood pressure observed previously after i.p. administration. Res ults using the methodology of food-reinforced operant conditioned beha vior are consistent with the interpretation that the ring hydroxylated derivatives, 4-hydroxy-phenyl-2-aminoethyl sulfide and 4-hydroxy-alph a-methyl-phenyl-2-aminoethyl sulfide, do not penetrate into the centra l nervous system. This finding supports our contention that the primar y site of action for the antihypertensive activity of the sulfides may be the peripheral adrenergic nerve ending. In view of the current hig h degree of interest in chiral development, the enantiomeric specifici ty of the antihypertensive activity of alpha-methyl-phenyl-2-aminoethy l sulfide was also evaluated. Results from these studies demonstrate t hat the (S)-enantiomer of alpha-methyl-phenyl-2-aminoethyl sulfide is more effective in lowering blood pressure after p.o. administration th an the (R)-enantiomer. The implications of our findings in terms of th e mechanism of action of these compounds are discussed.