s-16924 and ziprasidone

There is evidence that serotonergic mechanisms contribute to the functional profiles of antipsychotic drugs, several of which display affinity for human (h)5-HT(1A) receptors.. Here, we compared the interaction of several antipsychotic agents at h5-HT(1A) receptors employing mitogen-activated protein kinase (MAPK), an intracellular marker.. The influence of antipsychotics on MAPK phosphorylation was quantified in Chinese hamster ovary (CHO) cells stably transfected with h5-HT(1A) receptors by use of a highly selective antibody.. The novel antipsychotic agent, S16924, concentration-dependently (pEC(50), 8.10) stimulated the phosphorylation of MAPK. Its maximal effect (96%) was similar to that of the prototypical 5-HT(1A) agonist, (+)8-OH-DPAT (pEC(50), 8.54) (defined as 100%). The selective 5-HT(1A) receptor antagonist WAY100,635, which was inactive alone, abolished stimulation of MAPK by S16924 with a pK(b) of 9.66. This stimulatory influence of S16924 on MAPK was potently mimicked by the benzoisoxazole, antipsychotic ziprasidone (pEC(50), 7.25; 93%). The atypical antipsychotic clozapine also activated MAPK, albeit with lower potency and efficacy (pEC(50), 5.43 and 43%). These actions of ziprasidone and clozapine were also blocked by WAY100,635. Evaluated at a single, high concentration, several other antipsychotics stimulated MAPK phosphorylation with variable efficacy: quetiapine (75%), ocaperidone (74%), tiospirone (57%), olanzapine (54%) and risperidone (21%). In all cases, their actions were abolished by WAY100,635. In contrast, haloperidol, thioridazine and sertindole did not stimulate MAPK.. Antipsychotics display contrasting efficacies in modulating MAPK phosphorylation at h5-HT(1A) receptors, ranging from high (e.g. S16924 and ziprasidone), via intermediate (e.g. clozapine) to low (e.g. haloperidol). Differential modulation of 5-HT(1A) receptor-coupled MAPK may contribute to their contrasting functional profiles.

Topics: Animals; Antipsychotic Agents; CHO Cells; Clozapine; Cricetinae; Enzyme Activation; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Immunoblotting; Mitogen-Activated Protein Kinases; Phosphorylation; Piperazines; Pyrrolidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Thiazoles

Rats were trained to recognize a discriminative stimulus (DS) elicited by the dopamine D(2)/D(3) receptor agonist, PD128,907 (0.16 mg/kg, i.p.), which suppressed frontocortical release of dopamine (DA) but not 5-HT. The selective 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, dose-dependently generalized to PD128,907 with effective dose(50)s (ED50s) of 0.08 and 1.5mg/kg, s.c., respectively, and inhibited the release and synthesis of 5-HT but not of DA. The 'atypical' antipsychotic, clozapine, which displays weak partial agonist properties at 5-HT1A receptors, dose-dependently, though partially, generalized to PD128,907 (50%, 2.5mg/kg, s.c.). Further, S16924 and ziprasidone, which in a like manner, display partial agonist activity at 5-HT1A receptors, generalized with ED50s of 0.6 and 2.3mg/kg, s.c., respectively. In contrast, haloperidol, which is devoid of affinity at 5-HT1A sites, was inactive. At doses equivalent to those generalizing to PD128,907, clozapine, S16924 and ziprasidone reduced serotonergic (but not dopaminergic) transmission, whereas haloperidol was inactive. In rats trained to recognize a further D2/D3 agonist, 7-OH-DPAT (0.16 mg/kg, i.p.), generalization was obtained similarly with 8-OH-DPAT (ED50 = 0.07 mg/kg, s.c.), flesinoxan (3.4) and clozapine (0.6), but not with haloperidol. In conclusion, although PD128,907 and 7-OH-DPAT do not directly interact with 5-HT1A receptors or influence serotonergic transmission, their DS properties are mimicked by 5-HT1A receptor agonists at doses activating 5-HT1A but not D2/D3 (auto)receptors. These observations likely account for generalization of clozapine, S16924 and ziprasidone to PD128,907 and 7-OH-DPAT inasmuch as they behave as antagonists at D2/D3 receptors, yet agonists at 5-HT1A (auto)receptors.

Topics: Animals; Antipsychotic Agents; Benzopyrans; Clozapine; Discrimination Learning; Dopamine; Dopamine Agonists; Haloperidol; Humans; Male; Oxazines; Piperazines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Receptor Agonists; Tetrahydronaphthalenes; Thiazoles

5-HT(1A) receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [3H]WAY100,635 ([3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT(1A) receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTPgammaS (100 microM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTPgammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTPgammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTPgammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTPgammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [35S]GTPgammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT(1A) receptors, was less influenced by GTPgammaS. When the ratio of high-/low-affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [3H]-WAY100,635 binding by GTPgammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT(1A) receptors. These may contribute to differing profiles of antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Chlorpromazine; CHO Cells; Clozapine; Cricetinae; Dose-Response Relationship, Drug; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Haloperidol; Humans; Membranes; Piperazines; Piperidines; Pyridines; Pyrimidinones; Pyrrolidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Thiazoles; Thioridazine; Tritium