title: General pharmacological properties of the new angiotensin II receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. Part I: Effects on central nervous system and other properties.
abstract: The effects of TCV-116 ((+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate, CAS 145040-37-5), a nonpeptide angiotensin II receptor antagonist, on the central nervous and autonomic nervous systems, isolated smooth muscle and digestive system were investigated in various experimental animals. TCV-116 at 1000 mg/kg (p.o.) produced a slight decrease in body tone in mice, but at 300 mg/kg did not affect spontaneous locomotor activity, skeletal muscle coordination, tonic extensor convulsions, pentobarbital-induced sleeping time, frequency of acetic acid-induced writhing, or body temperature in mice or rats. TCV-116 (at 300 mg/kg p.o.) did not affect the spontaneous EEG in conscious, unrestrained cats, or (at 100 mg/kg i.d.) the spinal reflex in anesthetized cats. CV-11974, the active metabolite of TCV-116, did not inhibit neuromuscular transmission in isolated rat phrenic nerve-diaphragm preparations (10(-5) mol/l and 10(-4) mol/l). In anesthetized cats, TCV-116 at 100 and 300 mg/kg (i.d.) slightly reduced the pressor response to carotid occlusion, but had no effect on the bradycardic response to stimulation of the cervical vagus nerve, contraction of the nictitating membrane induced by electrical stimulation of the cervical sympathetic preganglionic nerve, or the changes in blood pressure in response to acetylcholine, histamine, norepinephrine, or bradykinin. CV-11974 had no effect on agonist-induced contraction of guinea pig ileum. In isolated smooth muscle preparations, CV-11974 even at 10(-4) mol/l did not affect the spontaneous motility of the rabbit ileum or the rat uterus, or KCl-induced tension in guinea pig trachea. TCV-116 at 300 mg/kg (p.o.) had no significant effect on gastric emptying or intestinal transport of a semisolid meal in rats, or on gastric secretion in pylorus-ligated rats. TCV-116 (30-300 mg/kg p.o.) had no effect on carrageenin-induced paw edema in rats. The results suggest that TCV-116 exerts no notable pharmacological effects on the central nervous system, autonomic nervous system, gastrointestinal function or smooth muscle function.
authors.affiliation: Department III, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Kito
authors.forename: S
authors.initials: S
authors.lastname: Morimoto
authors.forename: M
authors.initials: M
authors.lastname: Shiomi
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects*; D004064:Digestive System / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009132:Muscles / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013777:Tetrazoles
chemical_list: D000700:Analgesics; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil