EFFECTS OF CATECHOL RING FLUORINATION ON CARDIOVASCULAR AND RENAL ACTIVITIES OF FENOLDOPAM ENANTIOMERS

SK&F 87516 is a potent DA1 receptor agonist with demonstrated renal va sodilator activity. SK&F 87516 is the 6-fluoro analog of another DA1 a gonist/renal vasodilator agent, fenoldopam. SK&F 87516 is a racemic mi xture of two enantiomers, SK&F(R)-87516 and SK&F(S)-87516, and like fe noldopam, the (R)-enantiomer is responsible for the biological activit ies of the racemate. SK&F(R)-87516 is diuretic in spontaneously hypert ensive rats and in dogs, whereas its enantiomer, SK&F(S)-87516 is inac tive. SK&F(R)-87516 increases glomerular filtration rate, an effect wh ich may account, in part, for its diuretic activity. Unlike fenoldopam , SK&F(R)-87516 is not associated with acute hypotensive activity, tac hycardia, or stimulation of the renin-angiotensin-aldosterone system. The activity differences between SK&F(R)-87516 and fenoldopam are not related to differences in DA1 agonist potency. The activity difference s may be due to the differing effects of fluorine and chlorine on the electron distribution in the catechol ring, resulting in an enhanced e ffect of SK&F(R)-87516 at alpha2-adrenoceptors. (C) 1994 Wiley-Liss, I nc.