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Heusler P, Newman-Tancredi A, Loock T, Cussac D: Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells. Eur J Pharmacol. 2008 Feb 26;581(1-2):37-46. Epub 2007 Nov 28.
Antipsychotic drugs act preferentially via dopamine D (2) receptor blockade, but interaction with serotonin 5-HT (1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h) D (2S) receptors and h5-HT (1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD (2S) and HA-h5-HT (1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD (2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD (2S) receptors, whereas aripiprazole potently internalised these receptors (> 50% relative efficacy). Among antipsychotics with combined D (2)/5-HT (1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S) 7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl] methyl ]-8-azabicyclo-[3.2.1] octane-3-methanamine (SSR181507) partially internalised HA-hD (2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl] me thyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) ethyl]-3-(cyclopent-1-enyl )-benzylamine (F15063) were inactive. At the HA-h5-HT (1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino) tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT (1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY100635). Most antipsychotics induced HA-h5-HT (1A) receptor internalisation, with an efficacy rank order: nemonapride> F15063> SSR181507> bifeprunox approximately SLV313 approximately ziprasidone> aripiprazole and potencies: SLV313> SSR181507 approximately F15063> bifeprunox approximately nemonapride approximately aripiprazole> ziprasidone. Interestingly, the internalisation induced by clozapine was only minimal, whereas aripirazole and bifeprunox were more potent for internalisation than for G-protein activation. These different profiles of antipsychotics for receptor internalisation may help to evaluate their potential therapeutic impact in the treatment of schizophrenia. |
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