Neuropharmacology of a new psychotropic 2,3-benzodiazepine.

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.

New central dopamine agonists.

Recently, the importance of the dopamine receptor agonists has increased in the treatment of parkinsonism, different endocrinological diseases and cardiovascular illness. In the therapy some well known drugs, derivatives of ergot groups e.g. bromocriptine, lisuride and pergolide, have been found useful. In the Institute for Drug Research numerous semi-synthetic elymoclavine derivatives were synthesized during the past years, and the influence of these new compounds on both the central and peripheral dopamine transmission was examined. Among the different ergot derivatives compound GYKI-32 887 seemed to be the most effective dopamine agonist and it was selected for preclinical investigation. The endocrinological effects and the pre- and postsynaptic dopamine receptor stimulant activity of this new compound are summarized. GYKI-32 887 was more potent than bromocriptine as regards its inhibitory effect on prolactin secretion and antiparkinsonian efficacy. Besides the strong dopamine receptor stimulant action this new ergoline compound, contrary to bromocriptine, inhibits the convulsive action of bicucullin. It may be assumed that the GABA receptor agonistic effect of GYKI-32 887 would be also valuable in the treatment of various form of dyskinesias.

The role of central dopamine (DA) receptors in the regulation of blood pressure.

GYKI-32 887 reveals an antihypertensive action, similar to that of the known ergoline derivatives, in conscious SH-rats, in anesthetized normotensive rats, and in cats. It exerts its action first of all by stimulation of the central DA-receptors and by this it reduces the sympathetic activity. The hypotensive effect cannot be detected after icv administration, but both the hypotension and bradycardia can be antagonized by sulpiride administered either icv or iv.

The effect of GYKI-32 887 on dopamine (D2) and serotonin (5-HT1 and 5-HT2) receptors.

Investigations were carried out with a dopamine agonist compound GYKI-32 887 to compare its binding capacity towards D2, 5-HT1 and 5-HT2 receptors. Synaptosomal membranes were prepared from corpus striatum, hippocampus and frontal cortex of rats. The tritiated ligands used were: 3H-spiperone for D2 and 5-HT2 receptors and 3H-5-HT for 5-HT1 receptors. Comparing the results obtained, IC50 and Ki values, one can conclude that GYKI-32 887 has higher affinity towards D2 receptors than serotonin ones and shows better selectivity than bromocriptine, the reference substance.

Further evidence for the neuroleptic-like activity of gamma-endorphin.

gamma-Endorphin inhibits the amphetamine-induced stereotypy in rats with an approximate ED50 of 0.3 mg/kg. SC. The anti-amphetamine effect of gamma-endorphin can be antagonized to a certain extent by both the dopamine receptor stimulant 2-bromo-ergocryptine and the opiate receptor antagonist naloxone.

Effect of thyrotropin-releasing hormone (TRH) and antidepressant agents on brain stem and hypothalamic multiple unit activity in the cat.

The EEG and MUA (multiple unit activity) of mesencephalic reticular formation (MRF), area hypothalami posterior (PH), and area hypothalami anterior (AH) were studied in chronically implanted freely moving cats. The effects of thyrotropin-releasing hormone (TRH) and some antidepressant agents were tested on neuronal activity. Desipramine and imipramine resulted in a dose-dependent decline of MUA of all structures with the most significant decrease of activity in PH. A single injection of TRH resulted in slight or moderate gross behavioral changes and vegetative excitation lasting for 30-50 min with variable MUA levels. In the course of repetitive TRH treatment on consecutive days the gross behavioral changes and the vegetative symptoms failed to develop by the 3rd or 4th day. By that time the MUA changes of PH and MRF showed similar characteristics in response to TRH administration which was observed following the injection of desipramine and imipramine. The drugs, except for TRH, induced a suppression of paradoxical sleep cycles.

The effect of anti-parkinsonian drugs on chlorpromazine-induced depression of operant behaviour.

Rats were conditioned in automatic Skinner boxes on a discrete trial avoidance-escape schedule. The chlorpromazine-induced conditioned reflex inhibition could be reversed by apomorphine and amantadine, but not by atropine, trihexyphenidyl and diethazine. These findings seem to provide an additional tool for differentiating the atropine-like and dopaminergic anti-parkinsonian drugs.

Cellular action of gastrointestinal polypeptide hormones.

The present state of chemistry, structure-activity relationship and cellular mode of action of gastrointestinal polypeptide hormones (gastrin, secretin, cholecystokinin-pancreozymin, caerulein and bombesin) are reviewed. Possible structure of polypeptide receptors and the mechanism of peptide--receptor interaction are described, and the role of acetylcholine and histamine in secretion discussed. The present data support the hormonal-receptor significance of cyclic nucleotides (cAMP, cGMP) in the cellular regulation of secretion.