ABSTRACT
1-(3-Chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 51189) is a new analogue of tofisopam. Due to the novel chemical structure this molecule displays a peculiar spectrum of pharmacological activity. In many respects tofisopam and its new analogue differ from the traditional 1,4-benzodiazepines, e.g. in that they possess selective anxiolytic action without muscle relaxant and anticonvulsive activity, as well as they do not show any affinity for the 1,4-benzodiazepine receptors. This new compound exerts more pronounced anxiolytic potency than tofisopam. In addition to its main action it possesses significant antidepressant activity. It attenuates psychomotor agitation and exerts significant antiaggressive effect by reducing both spontaneous and induced aggressiveness. Vegetative responses (rise in blood pressure and heart rate) induced by electric stimulation of the hypothalamus are also inhibited by this compound, while motor functions remain unaffected and no somnolence is induced. The new tofisopam analogue fails to exert any potentiating effect either on ethanol or on barbiturates. GYKI-51189 has a highly favourable therapeutic index and only few side effects. Neither tolerance nor dependence was observed during the chronic toxicological investigations.
Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Aggression/drug effects , Animals , Anti-Anxiety Agents/toxicity , Anticonvulsants , Antidepressive Agents , Benzodiazepines/toxicity , Brain Chemistry/drug effects , Cats , Electroencephalography , Female , Hexobarbital/pharmacology , Male , Mice , Motor Activity/drug effects , Psychomotor Performance/drug effects , Rats , Sleep/drug effects , Species Specificity , Time FactorsABSTRACT
Several conventionally used in vivo pharmacological assays were applied to examine whether morphine (M) and a potent enkephalin analogue, [D-Met2,Pro5]enkephalinamide (DMPEA) have haloperidol (H)-like neuroleptic activity. The apomorphine (A)-induced stereotypy and the conditioned reflex activity were inhibited by extremely low doses of H, while somewhat higher doses were needed to induce catalepsy or to suppress the A-elicited turning behaviour in rats with unilateral nigral lesion. M produced these effects only in doses higher than needed for analgesia. DMPEA, however, attenuated the A-elicited stereotypy already at a subanalgesic dose level but it was very weak in the other tests. Furthermore, neither M nor DMPEA inhibited the A-elicited stereotypy completely. Consequently, these drugs exhibit strikingly dissimilar relative potencies in the in vivo assays considered specific for neuroleptics. Our findings, in accordance with much of the data available, suggest that neither M nor DMPEA has a specific neuroleptic activity.
