Exploring S 16924: A Comparative Study on Receptorial and Neurochemical Profiles with Clozapine and Haloperidol for Antipsychotic Potential

S 16924 exhibits a diverse interaction profile with over 20 native and cloned human monoaminergic receptors, resembling clozapine and contrasting with haloperidol. It demonstrates moderate binding to human D2 and D3 receptors and a notably higher affinity for the human D4 receptor. Using a [35S]GTPgammaS binding assay, S 16924, along with clozapine and haloperidol, acts as an antagonist at these receptors. S 16924, like clozapine, has a strong affinity for human 5-HT2A and 5-HT2C receptors but differs significantly with its high affinity for human 5-HT1A receptors. In a [35S]GTPgammaS binding model, S 16924 and clozapine function as partial agonists at these receptors, while haloperidol shows no activity.

In vivo studies reveal that S 16924 acts as an agonist at 5-HT1A autoreceptors, effectively inhibiting serotoninergic neuronal firing in the raphe region, an effect that can be reversed by the 5-HT1A antagonist WAY 100,635. Clozapine and haloperidol have a weaker impact on neuronal firing and are not affected by WAY 100,635. S 16924 also more potently reduces serotonin turnover in the striatum compared to clozapine or haloperidol.

Regarding dopaminergic transmission, S 16924 shows only a slight blockage of the inhibitory effect of the dopamine agonist apomorphine on dopaminergic neuronal firing, and it weakly increases dopamine turnover in various brain regions. Clozapine shows similar weak activity, while haloperidol, due to its higher D2 and D3 receptor affinity, is more potent.

In the frontal cortex of rats, S 16924 reduces serotonin levels and increases dopamine and NAD levels in a dose-dependent manner. However, it only suppresses serotonin levels in the striatum and nucleus accumbens without affecting dopamine levels there. Clozapine replicates this selective increase in frontal cortex dopamine levels compared to the striatum and accumbens, while haloperidol uniformly raises dopamine levels across these regions.

Finally, the influence of S 16924 on serotonin, dopamine, and NAD levels in the frontal cortex is diminished by WAY 100,635. Overall, S 16924 has a unique interaction profile at monoaminergic receptors, similar to clozapine but distinct from haloperidol, and acts as a potent, partial agonist at 5-HT1A receptors. Its acute administration decreases brain serotonin transmission and selectively enhances frontocortical dopamine transmission, suggesting a unique potential for antipsychotic activity as indicated in accompanying behavioral studies.