General pharmacology of the anxiolytic compound metaclazepam in comparison to other benzodiazepines.
7-Bromo-5-(2-chlorophenyl)-2,3-dihydro-2-(methoxymethyl)-1H-1,4- benzodiazepine X HCl (metaclazepam, KC-2547, Ka-2547, Talis) is a novel 1,4-benzodiazepine characterized by a high selectivity of its anxiolytic effects. The present experiments were performed to contribute to its general pharmacological profile and to evaluate possible risks especially on the cardiovascular field in comparison to standard benzodiazepines. The experiments were performed in guinea pig isolated ileal and papillary muscle preparations, anesthetized cats and dogs, conscious renal hypertensive (RHR) and pithed rats. At intravenous, intraduodenal and repeated oral administration of metaclazepam in anesthetized cats and dogs and RHR arterial hypotension, if any, occurred only at rather high dosages. Tilting experiments in dogs did not show any risk for postural hypotension due to metaclazepam. In guinea pig papillary muscles and in anesthetized dogs (i.v.), metaclazepam had a moderate negative inotropic effect. A diminution of stroke volume was seen only at high i.v. doses whereas cardiac output was maintained nearly constant by an increase in heart rate. In guinea pig papillary muscles metaclazepam, like diazepam, had only a tendency to prolong the refractory period. Unlike diazepam, i.v. metaclazepam had no relevant depressant effect on respiration in anesthetized cats. No specific interaction of metaclazepam with alpha- or beta-adrenoceptors was found in pithed rats and anesthetized cats. The papaverine-like, unspecific spasmolytic profile in the guinea pig isolated ileum suggests that metaclazepam has no relevant antimuscarinic properties. In anesthetized cats neither metaclazepam nor diazepam showed an effect on neuromuscular transmission; metaclazepam caused a markedly weaker inhibition of the polysynaptic linguomandibular reflex than diazepam and did not influence the monosynaptic patellar reflex. In conclusion, the results with metaclazepam did not indicate side effects limiting its therapeutic use as an anxiolytic. Its potential in producing untoward side effects on the cardiovascular and respiratory systems and its central muscle relaxant properties appear to be considerably weaker than with diazepam or bromazepam. Substantial overdosage may result in hypotension and/or impairment of cardiac contractility.
Buschmann
G
G
Kühl
U G
UG
Rohte
O
O
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002415:Cats; D003655:Decerebrate State; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006977:Hypertension, Renal / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D009541:Nictitating Membrane; D010210:Papillary Muscles; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D014151:Anti-Anxiety Agents; D011941:Receptors, Adrenergic; D001569:Benzodiazepines; C036366:metaclazepam