Abstract
The novel, potential antipsychotic, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide), displayed ∼25-fold higher affinity at human (h) dopamine D3 versus hD2L (long isoform) and hD2S (short isoform) receptors (pKi values, 8.7, 7.1, and 7.3, respectively). Conversely, haloperidol, clozapine, olanzapine, and risperidone displayed similar affinities for hD3, hD2L, and hD2S sites. In guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]-GTPγS) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD3 receptors, displaying pKB and pA2 values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD2L and hD2S receptors. Preferential antagonist properties of S33138 at hD3 versus hD2L receptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of Gαi3 recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected with hD3 and hD2L receptors that assemble into heterodimers, S33138 blocked (pKB, 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD4 receptors (<5.0) but revealed weak antagonist activity at hD1 receptors (Gαs/SPA, pKB, 6.3) and hD5 sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at human serotonin (5-HT)2A receptors (Gαq/SPA, pKB, 6.8, and inositol formation, 6.9) and at 5-HT7 receptors (adenylyl cyclase, pKB, 7.1). In addition, S33138 antagonized hα2C adrenoceptors ([35S]GTPγS, 7.2; Gαi3/SPA, 6.9; Gαo/SPA, 7.3, and extracellular-regulated-kinase, 7.1) but not hα2A or hα2B adrenoceptors (<5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible affinities for multiple subtypes of α1-adrenoceptor, muscarinic, and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically available antipsychotics, as a preferential antagonist at hD3 versus hD2 receptors.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126706.
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ABBREVIATIONS: EPS, extrapyramidal motor symptom; AR, adrenoceptor; H1, histamine; DA, dopamine; S33138 N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide; h, human; MDL100,907, R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol; SB269,970, (R)-1-{2-[1-(3-hydroxy benzensulfonyl) pyrrolidin-2-yl] ethyl}-4-methylpiperidine; RX821,002, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxan-2-yl)-4,5-dihydro-1H-imidazoline; SCH23390, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; CHO, chinese hamster ovary; [35S]GTPγS, guanosine-5′-O-(3-[35S]thio)-triphosphate; SPA, scintillation proximity assay; ERK, extracellular-regulated kinase; MAP, mitogen-activated protein; AC, adenylyl cyclase; Ro 20-1724, 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone; NA, noradrenaline; 5-HT, serotonin; IP, inositol phosphate; CGP-12177, 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one; SB414,796, trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))-phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; A437,203, 2-{3-4-(2-tert-butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]propyl-sulfanyl}-3H-pyrimidin-4-one.
- Received June 4, 2007.
- Accepted November 14, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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