Study of the novel non-xanthine heterocyclic compound GU285 as a potent non-selective adenosine receptor antagonist in the rat

• Published in: Arzneimittel-Forschung Vol. 52; no. 3; p. 175
• Main Authors: Harden, Fiona A, Brown, Lindsay, Quinn, Ronald J, Harrison, Glenn J, Headrick, John P, Rose'Meyer, Roselyn B, Willis, Roger J
• Format: Journal Article
• Language: English
• Published: Germany 01.01.2002
• Subjects: Animals; Blood Pressure - drug effects; Coronary Vessels - drug effects; Heart Atria - drug effects; Heart Rate - drug effects; In Vitro Techniques; Muscle, Smooth, Vascular - drug effects; Myocardial Contraction - drug effects; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar
• ISSN: 0004-4172
• DOI: 10.1055/s-0031-1299876

The novel pyrazolo[3,4-d]pyrimidine compound GU285 (4-amino-6-alpha-carbamoylethylthio-1- phenylpyrazolo[3,4-d]pyrimidine, CAS 134896-40-5) was examined for its ability (1) to inhibit binding of adenosine (ADO) receptor ligands in rat brain membranes, (2) to antagonise functional responses to ADO agonists in rat right and left atria and coronary resistance vessels, and (3) to reduce the fall in heart rate and arterial blood pressure produced by the ADO A1 agonist N6-cyclopentyladenosine (CPA) in the intact, anaesthetized rat. GU285 competitively inhibited binding of the ADO A1 agonist [3H]-R-N6-phenylisopropyladenosine (R-PIA) yielding a Ki value of 11 (7-18) nmol.l-1 (geometric mean +/- 95% Cl). When assayed against the ADO A2A selective agonist [3H]-2-[p-(2-carboxyethyl)- phenethylamino]-5'-N-ethylcarboxamidoadenosine, (CGS21680), a Ki of 15 (10-24) nmol.l-1 was obtained. In spontaneously beating right atria, GU285 competitively antagonized negative chronotropic effects of R-PIA with a pA2 of 8.7 +/- 0.3 and in electrically paced left atria, GU285 competitively antagonized negative inotropic effects of R-PIA with a pA2 of 9.0 +/- 0.1. In the potassium-arrested, perfused rat heart GU285 (1 mumol.l-1) antagonized only the high sensitivity, ADO A2B mediated component of the biphasic relaxation of the coronary vasculature produced by NECA. The low sensitivity component was unchanged. GU285 (1 mumol.kg-1) antagonized the negative chronotropic and hypotensive effects of the adenosine A1 agonist CPA in anaesthetized rats, producing a 10-fold rightward shift in the dose-response relationship. These data demonstrate that in the rat, GU285 is a potent, non-selective adenosine receptor antagonist that maintains its activity in vivo.