fk-453 and 1-3-dipropyl-8-cyclopentylxanthine

Novel 3-(2-cycloalkyl and cycloalkenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazo lo [1,5-a]-pyridines were synthesized and evaluated for their adenosine A1 receptor binding activities. In this series, FR166124 (3) was found to be the most potent and selective adenosine A1 receptor antagonist, and the double bond of the cyclohexenyl acetic acid group was essential for selectivity of A1 receptor binding. Furthermore, the solubility in water of the sodium salt of FR 166124 was high.

Topics: Antihypertensive Agents; Inhibitory Concentration 50; Molecular Structure; Piperidines; Purinergic P1 Receptor Antagonists; Pyrazoles; Pyridines; Receptors, Purinergic P1; Solubility; Structure-Activity Relationship; Water; Xanthines

The primary objective of this study was to test the hypothesis that endogenous adenosine/A1 receptor interactions participate in the normal regulation of the cardiovascular system and kidneys. In anesthetized rats, we examined the effects of pharmacologically equivalent doses of DPCPX and FK453 (two structurally dissimilar A1 receptor antagonists) and the effects of FR113452 (the less active enantiomer of FK453) on 20 hemodynamic and renal function parameters. After baseline measurements, animals were randomized to an intravenous infusion of either vehicle or DPCPX, FK453, or FR113452 (10, 30, and 30 micrograms/kg/min, respectively), and all measurements were repeated. Neither DPCPX, FK453, nor FR113452 affected significantly the heart rate; cardiac output; stroke volume; arterial blood pressure; total vascular resistance; regional blood flows to and regional vascular resistances of the carotid, mesenteric, renal, and hindquarter vascular beds; glomerular filtration rate; filtration fraction; or potassium excretion. However, DPCPX and FK453, but not FR113452, caused a pronounced diuresis (from 194 +/- 30 to 696 +/- 144 microliters/30 min for DPCPX, and from 386 +/- 76 to 814 +/- 156 microliters/30 min for FK453) and natriuresis (from 0.88 +/- 0.30 to 5.09 +/- 1.28 mumol/min for DPCPX, and from 1.58 +/- 0.56 to 5.09 +/- 1.02 mumol/min for FK453). These results firmly establish that (a) endogenous adenosine/A1 receptor interactions regulate renal excretory function, (b) this regulation is via a renal tubular, rather than hemodynamic, mechanism, and (c) A1 receptor antagonists caused diuresis without disturbing potassium homeostasis.

Topics: Animals; Antihypertensive Agents; Diuresis; Hemodynamics; Hemolysis; Male; Natriuresis; Purinergic Antagonists; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Renal Circulation; Xanthines

The purpose of the present study was to develop a pharmacological method for determining in the rat in vivo whether endogenous adenosine participates in a given process via activation of A1 adenosine receptors. In anesthetized rats, A1 receptors were activated by infusing the highly selective A1 receptor agonist N6-cyclopentyladenosine, and A2 receptors were stimulated by infusing the highly selective A2 receptor agonist CGS21680C. The bradycardic response to N6-cyclopentyladenosine and the hypotensive response to CGS21680C were used to assess A1 receptor and A2 receptor activation, respectively. After control responses to these purinergic agonists were elicited, animals were given infusions for several hours of either vehicle or one of six dosage levels of FK453 (a potent, selective, nonxanthine A1 receptor antagonist), one of three dosage levels of FR113452 (the S-enantiomer of FK453) or one of seven dosage levels of DPCPX (a potent, selective, xanthine A1 receptor antagonist). Antagonists were infused for > 4 hr, and at various times during the infusions, bradycardic and hypotensive responses to N6-cyclopentyladenosine and CGS21680C, respectively, were reassessed. Both FK453 and DPCPX were highly potent A1 receptor antagonists in vivo, and complete inhibition of bradycardic responses to N6-cyclopentyladenosine were obtained with 3 and 1 micrograms/kg/min, respectively. FR113452 was a very weak antagonist and only slightly reduced bradycardic responses to N6-cyclopentyladenosine at 100 micrograms/kg/min. In vivo FK453 and DPCPX were > 300 and 1000 times selective for the A1 receptor, respectively, compared with the A2 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Male; Phenethylamines; Purinergic Antagonists; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic; Stereoisomerism; Xanthines