General pharmacology of the new antimuscarinic compound vamicamide.
The general pharmacology of the new antimuscarinic compound vamicamide (FK176, (+/-)-(2R*, 4R*)-4-dimethylamino-2-phenyl-2- (2-pyridyl)valeramide, CAS 132373-81-0) was investigated using mice, rats, guinea pigs and dogs, and was in part compared with that of oxybutynin hydrochloride (oxybutynin, CAS 1508-65-2), a similar type of compound. 1. Vamicamide induced mydriasis after oral administration (p.o.) of 10 mg/kg or more, and suppressed defecation after 32 mg/kg or more in the general activity and behavior test with rats. 2. Vamicamide increased spontaneous locomotor activity in mice at 32 mg/kg or more (p.o.) and suppressed tonic convulsions in the electroconvulsive shock test with mice at 100 mg/kg. The compound at 10-100 mg/kg (p.o) did not show significant effects on hexobarbital-induced anesthesia, pentetrazole-induced convulsions and pain response by Haffner's method in mice, body temperature in rats or spontaneous electroencephalogram (EEG) in rabbits. On the other hand, oxybutynin increased high voltage slow waves of spontaneous EEG in rabbits at 32 mg/kg or more (p.o.) and prolonged hexobarbital-induced anesthesia time in mice at 100 mg/kg. 3. Vamicamide in concentrations of 0.001-1% (1 x 10(-4)-1 x 10(-1) g/ml) did not show local anesthetic effect on the corneal reflex test with guinea pigs. The compound in concentrations of 1 x 10(-5) and 1 x 10(-4) g/ml also had no effects on contractions of the isolated rat diaphragm caused by electrical stimulation of the phrenic nerve. 4. Vamicamide on the highest concentration of 1 x 10(-4) g/ml augmented contractions of isolated rat vas deferens induced by noradrenaline, resting tonus of the isolated guinea pig trachea, and contractile force of spontaneous movement of the isolated rat nonpregnant uterus. The compound at 1 x 10(-4) g/ml had no significant effects on KCl-induced contraction of the isolated rat thoracic aorta. 5. Vamicamide elevated systemic blood pressure and increased heart rate but had no effects on respiratory movement of the chest in conscious dogs at an oral dose of 10 mg/kg or more. The compound in intraduodenal (i.d.) doses of 3.2-32 mg/kg had no effect on femoral blood flow in anesthetized dogs. Vamicamide augmented contractile force and reduced beating rate in isolated guinea pig atria at a concentration of 1 x 10(-5) g/ml or more. Oxybutynin increased heart rate at 3.2 mg/kg or more (p.o.), and elevated blood pressure at 10 mg/kg or more in conscious dogs. 6. Vamicamide slightly inhibited small intestinal transit in rats at 3.2 mg/kg or more (p.o.). On the other hand, oxybutynin inhibited the transit in rats at 0.32 mg/kg or more. 7. Vamicamide had no effects on urine volume, urinary excretion of Na+, K+, Cl- and uric acid in rats at an oral dose of 100 mg/kg or less, or on renal function in anesthetized dogs at an i.d. dose of 32 mg/kg or less. 8. Vamicamide showed no effects on bleeding time in mice at 100 mg/kg p.o., rabbit platelet aggregation induced by adenosine diphosphate or collagen at 1 x 10(-4) g/ml, blood coagulation systems in rats at 100 mg/kg p.o., or hemolysis on rabbit blood at a concentration of 1% or less. Thus, vamicamide in the doses used inhibited gastrointestinal motility, and caused mydriasis as effects possibly due to its anticholinergic action. The compound had no effects on the central nervous system, cardiovascular system, renal functions, or blood system.
Yamamoto
T
T
Pharmacological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan.
Honbo
T
T
Tokoro
K
K
Kojimoto
Y
Y
Kodama
R
R
Ohtsuka
M
M
Shimomura
K
K
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists / Q000097:blood / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000097:blood / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects
D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D011725:Pyridines; C005419:oxybutynin; C083702:vamicamide