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 vasodilator activity. SK&F 87516 is the 6‐fluoro analog of another DA1 agonist/renal vasodilator agent, fenoldopam. SK&F 87516 is a racemic mixture of two enantiomers, SK&F(R)‐87516 and SK&F(S)‐87516, and like fenoldopam, the (R)‐enantiomer is responsible for the biological activities of the racemate. SK&F(R)‐87516 is diuretic in spontaneously hypertensive rats and in dogs, whereas its enantiomer, SK&F(S)‐87516 is inactive. SK&F(R)‐87516 increases glomerular filtration rate, an effect which may account, in part, for its diuretic activity. Unlike fenoldopam, SK&F(R)‐87516 is not associated with acute hypotensive activity, tachycardia, 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 differences may be due to the differing effects of fluorine and chlorine on the electron distribution in the catechol ring, resulting in an enhanced effect of SK&F(R)‐87516 at α2‐adrenoceptors. © 1994 Wiley‐Liss, Inc.