Comparative Functional Profiling of S 16924: A Novel Antipsychotic with 5-HT1A Agonist Properties Against Clozapine and Haloperidol

The compound S 16924 showed promising effects in various models related to the management of schizophrenia symptoms. It effectively reduced the movement triggered by dizocilpine and cocaine, as well as the avoidance responses and climbing behavior induced by apomorphine. Its median inhibitory dose was comparable to that of clozapine but higher than haloperidol. Both S 16924 and clozapine demonstrated similar potency in blocking rotations caused by D1 and D2 agonists, unlike haloperidol which was more selective.

S 16924 was notably more effective in inhibiting head-twitches caused by DOI and movement induced by phencyclidine compared to its effect on amphetamine-induced movement. Clozapine showed a similar trend, while haloperidol did not. The compound also effectively blocked the discriminative stimulus properties of DOI, as did clozapine, but haloperidol was ineffective.

In terms of generalizing to the discriminative stimulus of clozapine, S 16924 fully mimicked it at a lower dose than clozapine itself, while haloperidol only partially did so. Analysis of EEG power spectra indicated that S 16924 and clozapine both enhanced frequencies in the 7 to 8 Hz range, whereas haloperidol favored the 10 to 14 Hz range.

In cognitive-attentional function tests, S 16924 and clozapine induced significant latent inhibition, an effect not observed with haloperidol. Furthermore, all three substances were able to block the disruption of latent inhibition caused by amphetamine, but at higher doses.

Catalepsy, a side effect often associated with traditional antipsychotics, was not induced by S 16924 or clozapine, unlike haloperidol. Additionally, S 16924 and clozapine were found to inhibit the induction of catalepsy by haloperidol, with S 16924's action being reversed by the 5-HT1A receptor antagonist WAY 100,635.

In terms of side effects, gnawing behavior induced by methylphenidate was inhibited by all three substances, but only S 16924's effect was blocked by WAY 100,635. Haloperidol significantly increased prolactin levels, while S 16924 and clozapine had a less pronounced effect.

Clozapine showed high affinity for muscarinic and histamine receptors, a characteristic not shared by S 16924 or haloperidol, which had low affinity for these receptors. Overall, S 16924 exhibited a profile similar to clozapine in diverse models, indicating potential antipsychotic properties with a lower risk of inducing extrapyramidal side effects, particularly catalepsy.