S-16924, a Novel, Potential Antipsychotic with Marked Serotonin1A Agonist Properties. IV. A Drug Discrimination Comparison with Clozapine
- Mark J. Millan,
- Rudy Schreiber,
- Sabine Monneyron,
- Brigitte Denorme,
- Christophe Melon,
- Sophie Queriaux and
- Anne Dekeyne
- Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France
Abstract
The novel benzodioxopyrrolidine (S-16924) displays a clozapine-like profile of interaction with multiple monoaminergic receptors, in addition to potent agonist activity at serotonin (5-HT)1A receptors. S-16924 (2.5 mg/kg i.p.) and clozapine (5.0 mg/kg i.p.) generated robust discriminative stimuli (DS) and displayed full mutual generalization. The D4 antagonists L-745,870 and S-18126, the D1/D5antagonist SCH-39166, and the D3 antagonist S-14297 showed at most partial generalization to S-16924 and clozapine. The D2/D3 antagonist raclopride fully generalized to S-16924, but only partially generalized to clozapine. The 5-HT2A antagonist MDL-100,907 fully generalized to S-16924 and two further 5-HT2A antagonists, fananserin and SR-46349, showed partial generalization. However, MDL-100,907, fananserin, and SR-46349 showed less pronounced generalization to clozapine. Similarly, the 5-HT2C antagonists SB-200,646 and SB-206,553 more markedly generalized to S-16924 than to clozapine. The 5-HT1A receptor agonist (±)-8-dihydroxy-2-(di-n-propylamino) tetralin generalized fully to S-16924 but not to clozapine. Full generalization was obtained to both S-16924 and clozapine for the clozapine congeners, olanzapine and quetiapine. In distinction, the benzisoxazole, risperidone, and the phenylindole, sertindole, weakly generalized to S-16924 and clozapine. However, the benzisoxazole ziprasidone, which possesses 5-HT1A agonist properties, generalized fully to S-16924 but not to clozapine. Finally, the muscarinic antagonist scopolamine generalized fully to clozapine and partially to S-16924. In conclusion, S-16924 and clozapine display both communalities and differences in their “compound” DS; this likely reflects their respective complex patterns of interaction with multiple monoaminergic receptors. Although no specific receptor was identified as underlying the clozapine DS, 5-HT1A agonist as well as D2 and 5-HT2A/2C antagonist properties contribute to the S-16924 DS.
Footnotes
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Send reprint requests to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290 - Croissy-sur-Seine, Paris, France.
- Abbreviations:
- AR
- adrenoceptor
- DS
- discriminative stimulus
- 5-HT
- serotonin
- RR
- response rate
- (±)-8-OH-DPAT
- (±)-8-dihydroxy-2-(di-n-propylamino)tetralin
- L-745
- 870, 3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine
- MDL-100
- 907, [R(+)-α-(2,3dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol]
- ORG-5222
- {trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
- SB-200
- 646, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea
- SB-206
- 553, 5 methyl-1-(3-pyridil-carbamoyl)1,2,3,5-tetrahydropyrrolo[2,3-f]indole
- SCH-39166
- (−)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxyl-N-methyl-5H-benzo[d]naphto-[2,1-benazazepine]
- SR-46349
- {1(Z)-[2-(dimethylamino)ethoxyimino]}-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene]
- (±)-S11566
- {(±)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b)dihydro,2,3-furane]}
- (+)-S-14297
- {(+)-[7-(N,N-dipropylamino)5,6,7,8-tetrahydro-naphto(2,3b)dihydro,2,3-furane]}
- S-16924
- (R)-2-{1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluorophenyl)ethanone
- S-18126
- {2-[4-(2,3-dihydrobenzo [1,4]dioxin-6-yl)piperazin-1-yl methyl]indan- 2-yl} methanol
- WAY-100
- 635, (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclo-hexanecarboxamide
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- Received July 7, 1998.
- Accepted November 24, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
