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.