5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists), 5-HT2A receptor antagonists(Serotonin 2a (5-HT2a) receptor antagonists), D2 receptor antagonists(Dopamine D2 receptor antagonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Psychotic Disorders

Originator Organization

Servier Pharmaceuticals LLCStartup

Active Organization-

Inactive Organization

Servier Pharmaceuticals LLCStartup

Drug Highest PhaseDiscontinuedDiscovery

First Approval Date-

Regulation-

100 Clinical Results associated with S-16924

100 Translational Medicine associated with S-16924

100 Patents (Medical) associated with S-16924

Literatures (Medical) associated with S-16924

01 Sep 2003·Naunyn-Schmiedeberg's archives of pharmacologyQ4 · MEDICINE

Comparison of hippocampal G protein activation by 5-HT 1A receptor agonists and the atypical antipsychotics clozapine and S16924

Q4 · MEDICINE

Article

Author: Rivet, J.-M. ; Marini, L. ; Millan, M. J. ; Touzard, M. ; Newman-Tancredi, A. ; Cussac, D. ; Chaput, C.

This study employed [(35)S]guanosine 5'- O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT(1A) receptors with those of reference agonists at postsynaptic 5-HT(1A) receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, E(max), values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC(50)) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT(1A) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT(1A) receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding, consistent with partial agonist properties. In [(35)S]GTPgammaS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT(1A) receptors, was more potent in the septum (pEC(50) approximately 6.5) than in the dentate gyrus of the hippocampus (pEC(50) approximately 5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 microM) did not enhance [(35)S]GTPgammaS labelling in any structure, S16924 (10 micro M) modestly increased [(35)S]GTPgammaS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 microM)-stimulated [(35)S]GTPgammaS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT(1A) receptors in the hippocampus. These data support a role of postsynaptic 5-HT(1A) receptors in the functional profiles of certain antipsychotic agents.

01 Apr 2003·NeuropharmacologyQ2 · MEDICINE

Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907

Q2 · MEDICINE

Article

Author: Iob, L. ; Dekeyne, A. ; Millan, M. J.

Employing a two-lever, food-reinforced FR10 procedure, rats were trained to recognize a discriminative stimulus (DS) elicited by the 5-HT(2A) receptor antagonist and potential antipsychotic agent, MDL100,907 (0.16 mg/kg, i.p.). In generalization tests, by analogy to MDL100,907 itself (Effective Dose(50) (ED(50)), 0.002 mg/kg, s.c.), the 'atypical' antipsychotic, clozapine, which displays high affinity for 5-HT(2A) as compared to D(2) receptors, dose-dependently and fully generalized to MDL100,907 (ED(50), 0.2 mg/kg, s.c.). S16924 (0.05 mg/kg, s.c.), S18327 (0.09 mg/kg, s.c.), quetiapine (1.8 mg/kg, s.c.), risperidone (0.02 mg/kg, s.c.) and ziprasidone (0.01 mg/kg, s.c.), antipsychotics which possess-like clozapine-marked affinity for 5-HT(2A) versus D(2) receptors, also generalized to MDL100,907. In distinction, raclopride, an antipsychotic which selectively interacts with D(2) versus 5-HT(2A) receptors, did not display significant generalization. Interestingly, haloperidol, which shows only modest affinity for 5-HT(2A) versus D(2) sites, generalized to MDL100,907 (ED(50), 0.02 mg/kg, s.c.). In light of the antagonist properties of haloperidol, clozapine and all other antipsychotics tested (except raclopride) at alpha(1)-adrenoceptors (ARs), the selective alpha(1)-AR antagonists, prazosin and WB4101, were examined. Both dose-dependently and fully generalized to MDL100,907 (ED(50)s, 0.07 and 0.11 mg/kg, s.c., respectively). At doses showing pronounced generalization to MDL100,907, the only drugs which significantly suppressed response rates were haloperidol and, weakly, quetiapine. Raclopride also markedly decreased response rates. In conclusion, the antipsychotic agents, clozapine, ziprasidone, risperidone, S16924, S18327, quetiapine and haloperidol, all generalized to a DS elicited by MDL100,907. While D(2) receptors are not implicated in their actions, in addition to antagonist properties at 5-HT(2A) receptors, blockade of alpha(1)-ARs and other, as yet unidentified, mechanisms may be involved. These data underpin interest in MDL100,907 as a potential antipsychotic agent.

01 Jul 2002·PsychopharmacologyQ3 · MEDICINE

Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)1A receptors

Q3 · MEDICINE

Article

Author: Millan, Mark J. ; Duqueyroix, Delphine ; Cussac, Didier ; Newman-Tancredi, Adrian

RATIONALE:

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.

OBJECTIVE:

Here, we compared the interaction of several antipsychotic agents at h5-HT(1A) receptors employing mitogen-activated protein kinase (MAPK), an intracellular marker.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

100 Deals associated with S-16924

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Indication	Highest Phase	Country/Location	Organization	Date
Psychotic Disorders	Discovery	FR	Servier Pharmaceuticals LLCStartup	-

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