title: General pharmacology of the new non-xanthine adenosine A1 receptor antagonist (+)-(R)-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2- piperidine ethanol.
abstract: FK 453 ((+)-(R)-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol, CAS 121524-18-3) is a potent non-xanthine adenosine A1 receptor antagonist with diuretic and renal vasodilatory activity. The general pharmacology of FK 453 was investigated in mice, rats, guinea-pigs and dogs. In in vivo tests, FK 453 had little effect on the central nervous system (general behaviour, spontaneous motor activity, potentiation of barbiturate anesthesia, anticonvulsant activity, analgesic activity and body temperature), hematological system (bleeding time, coagulation time and recalcification time) and intestinal charcoal transit. FK 453 also did not show any cardiovascular (blood pressure, heart rate and femoral blood flow) or respiratory effects. In in vitro tests, although FK 453 had little effect on noradrenaline-induced contraction in rat vas deferens and histamine-induced contraction in guinea-pig trachea, FK 453 inhibited the acetylcholine-, histamine- and barium-induced contraction in isolated guinea-pig ileum and serotonin-induced contraction in isolated rat stomach. FK 453 also exerted significant inhibitory activity on collagen- and U 46619-induced platelet aggregation. However these effects of FK 453 on isolated tissue and platelet were observed only at high concentrations. These results suggest that FK 453 possesses a selective pharmacological profile, and one promising therapeutic site for this drug is in the kidney.
authors.affiliation: Toxicology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Terai
authors.forename: T
authors.initials: T
authors.lastname: Kusunoki
authors.forename: Y
authors.initials: Y
authors.lastname: Kita
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: A
authors.initials: A
authors.lastname: Akahane
authors.forename: Y
authors.initials: Y
authors.lastname: Shiokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kohno
authors.forename: H
authors.initials: H
authors.lastname: Horiai
authors.forename: J
authors.initials: J
authors.lastname: Mori
authors.forename: Y
authors.initials: Y
authors.lastname: Mine
authors.forename: M
authors.initials: M
authors.lastname: Kohsaka
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009130:Muscle, Smooth / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012137:Respiratory System / Q000187:drug effects
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D000959:Antihypertensive Agents; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; C077100:FK 453