Vol. 286, Issue 3, 1356-1373, September 1998

S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)_1A Agonist Properties: II. Functional Profile in Comparison to Clozapine and Haloperidol

Mark J. Millan, Rudy Schreiber, Anne Dekeyne, Jean-Michel Rivet, Karin Bervoets, Michaelis Mavridis, Claude Sebban¹, Sophie Maurel-Remy, Adrian Newman-Tancredi, Michael Spedding, Olivier Muller, Gilbert Lavielle and Mauricette Brocco

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290-Croissy-sur-Seine, Paris, France

S 16924 antagonized locomotion provoked by dizocilpine and cocaine, reduced conditioned avoidance responses and blocked climbing elicited by apomorphine, models predictive of control of the positive symptoms of schizophrenia: its median inhibitory dose (ID)₅₀ was 0.96 mg/kg, s.c. vs. 1.91 for clozapine and 0.05 for haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D₁ agonist, SKF 38393, and by the D₂ agonist, quinpirole, was blocked equipotently by S 16924 (0.8 and 1.7) and clozapine (0.6 and 2.0), whereas haloperidol preferentially blocked quinpirole (0.02) vs. SKF 38393 (1.8). S 16924 more potently inhibited the head-twitches elicited by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by phencyclidine than it inhibited the locomotion elicited by amphetamine (ID₅₀s = 0.15 and 0.02 vs. 2.4). Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not haloperidol (0.07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by S 16924 (ID₅₀ = 0.17) and clozapine (0.05) but not by haloperidol (>0.16). S 16924 fully (100%) generalized [effective dose (ED)₅₀ = 0.7] to a clozapine DS and clozapine (0.23) fully generalized to a S 16924 DS whereas haloperidol (0.08) only partially generalized (50%) to their DS in each case. Power spectra analysis of electroencephalograms from frontal cortex showed that both S 16924 (2.0) and clozapine (5.0) reinforced frequencies in the 7 to 8 Hz range whereas haloperidol (0.5) preferentially reinforced frequencies in the 10 to 14 Hz range. In a model of perturbation of cognitive-attentional function, significant latent inhibition was obtained with S 16924 (0.08) and clozapine (0.16), but not haloperidol (0.0063 and 0.04): higher doses of S 16924 (2.5), clozapine (5.0) and haloperidol (0.1) all blocked disruption of latent inhibition by amphetamine (1.5). Catalepsy was provoked by haloperidol (0.04-0.63) but not by S 16924 (80.0) or clozapine (80.0). Further, S 16924 (ID₅₀ = 3.2) and clozapine (5.5) inhibited induction of catalepsy by haloperidol. This action of S 16924 was abolished by the 5-HT_1A receptor antagonist, WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of clozapine. Further, although gnawing elicited by methylphenidate was inhibited by S 16924 (ID₅₀ = 8.4), clozapine (19.6) and haloperidol (0.04), only the action of S 16924 was blocked by WAY 100,635 (0.16). Haloperidol potently (0.01-0.16, ~24-fold) increased prolactin levels whereas they were less markedly affected by S 16924 (2.5-40.0, 4-fold) and clozapine (10.0-40.0, 3-fold). Clozapine displayed high affinity at cloned, human, muscarinic (M₁) and native, histamine (H₁) receptors (K_is = 4.6 and 5.4 nM, respectively), whereas S 16924 (>1000 and 158) and haloperidol (>1000 and 453) displayed low affinity. In conclusion, S 16924 displays a profile of activity in diverse models of potential antipsychotic and extrapyramidal properties similar to that of clozapine and different to that of haloperidol. In particular, reflecting its partial agonist actions at 5-HT_1A receptors, S 16924 inhibits rather than induces catalepsy in rats. However, in contrast to clozapine, S 16924 displays only low affinity for muscarinic and histaminic receptors.