Marton Fekete

Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models

The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5‐HT2A and 5‐HT2C receptors (Ki = 8.7–27 nM/l). Deramciclane had also a moderate affinity to dopamine D2 and sigma receptors but did not interact with any of the adrenergic receptors.

Autoradiographic localization and quantitative determination of specific binding sites of anxiolytic homophthalazines (formerly called 2,3-benzodiazepines) in the striato-pallido-nigral system of rats

Homophthalazines (2,3-benzodiazepin-derivates, such as tofisopam, nerisopam, girisopam) constitute a drug family with strong anxiolytic and antipsychotic potencies. By autoradiography, all of these drugs showed a specific distribution pattern of binding sites exclusively in brain areas which relate to the striato-pallido-nigral system, while no specific label was found in any other brain areas in the rat. Quantitative analyses of the autoradiograms by computerized densitometry, as well as by a receptor binding assay on 32 microdissected brain areas showed very high concentrations of tritiated homophthalazines in the glubus pallidus, caudate nucleus, putamen and the substantia nigra. Relatively high density of binding sites was measured in the nucleus accumbens, the olfactory tubercle, the entopeduncular nucleus and the subthalamic nucleus. Concentrations measured in the cerebral cortical areas, cerebellum or brainstem nuclei did not differ from the background. No significant differences were found between the homophthalazines investigated in terms of the distribution patterns or density of binding sites.

A novel specific binding site for anxiolytic homophthalazines in the rat brain

Radioligand binding studies were performed in order to elucidate the mechanism of action of anxiolytic‐neuroleptic homophthalazines. Rat striatal membrane preparations were found to bind 3H‐EGIS 6775 [3H‐GYKI‐52 322, 3H‐(I‐(4‐aminophenyl)‐4‐methyl‐7,8‐dimethoxy‐5H‐homophthalazine)] in a specific and displaceable manner. Several other brain regions tested were devoid of similar binding activity. Saturation analysis revealed that binding affinity was in the 10−5‐10−7 M range. Binding was enhanced by Mg2+ ions and, to a smaller extent by Ca2+ ions. The binding principle was sensitive to heat or trypsin treatment. This specific binding site appears, according to competition studies, different from the receptors whose presence in the rat striatum has been reported earlier.

Changes in specific binding sites of girisopam after chemical and surgical lesions in the striato-nigral system

Neurotoxin (AMPA)-induced lesions in the caudate nucleus as well as unilateral surgical transection of the striato-nigral pathway strongly depleted the binding of a homophthalazine (formerly called 2,3-benzodiazepines) girisopam (GYKI-51189, EGIS 5810) selectively in the substantia nigra of the rat, ipsilateral to the lesions. In contrast to this, AMPA injections into the substantia nigra failed to effect on girisopam binding to either components of the nigro-striatal system. Data indicate that this homophthalazine may bind to a descending component of the striatum (striato-nigral projecting neurons), or its binding capacity to substantia nigra neurons depends on the integrity of striatal afferent pathways to the substantia nigra.

Selective interaction of homophtalazine derivatives with morphine

Homophtalazines show specific binding sites in the nigrostriatal system and to find their target of action the interactions between these derivatives, nerisopam and girisopam, and chlorpromazine, chlordiazepoxide and morphine were assessed. The compounds did not influence the chlorpromazine induced decrease in motility and catalepsy, nor did they alter the antiaggressive and anticonvulsive action of chlordiazepoxide. However, nerisopam and girisopam augmented the agonist potency of morphine to induce catalepsy or analgesia; they also altered the opioid antagonist potency of naloxone. The naloxone-induced decrease in sucrose consumption in drinking water was augmented by nerisopam and girisopam. It is suggested that a possible target of action of homophtalazines is the opioid signal transduction.