FK453: A Novel Non‐Xanthine Adenosine A1 Receptor Antagonist as Diuretic

Abstract

Adenosine is a purine nucleotide that is widely distributed throughout the body; it modulates a wide variety of physiological functions via extracellular receptors. Adenosine receptors, located on the cell membranes, are classified into two major subtypes, adenosine A, and A, receptors. This classification was originally based on the effects of a series of adenosine analogs on adenylate cyclase activity; activation of the adenosine A, receptor inhibits, while activation of the adenosine A2 receptor stimulates, adenylate cyclase (26,46). Many adenosine agonists that have a preferential affinity for adenosine A, receptors depress heart rate, myocardial contractility. and impulse conduction velocity (5,10,14). The agonists that have a greater affinity for adenosine A, receptors induce vasodilation ( 1 1.15,17,24,28). A number of workers have found that another adenosine receptor, which has been classified as an adenosine A , receptor, is present in many tissues. This receptor was recently subdivided into adenosine A, and A, receptor subtypes. As knowledge of the different types of adenosine receptors increases, these receptors may prove to be possible targets for novel pharmacologically active drugs. Adenosine itself is used in the acute treatment and diagnosis of supraventricular arrhythmias. To date, however, no selective adenosine receptor agonist or antagonist has been used therapeutically. FK453 is a novel pyrazolopyridine derivative that was synthesized at Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). During a search for diuretics, FK453 was found to possess a potent diuretic activity with renal vasodilatory and uricosuric effects (40). In addition. FK453 markedly antagonized the negative inotropic effects of adenosine in isolated guinea pig atria, but was less potent in inhibiting the relaxation induced by adenosine in guinea pig aorta. These results suggested that FK453 is a potent and selective