P.3.d.004 F15063, a novel antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: I. Receptor affinity and efficacy in vitro and activity in neurochemical and neuroendocrine tests in rodents

Newman‐Tancredi, Adrian; Assié, Marie Bernadette; Martel, J.C.; Cosi, Cristina; Heusler, Peter; Slot, L. Bruins; Carilla-Durand, E.; Cussac, Didier

doi:10.1016/s0924-977x(06)70551-x

Cited by 8 publications

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“…Competition binding experiments were carried out by using radioligands, buffers and incubation conditions described previously (Newman‐Tancredi et al. , 2007).…”

Section: Methodsmentioning

confidence: 99%

“…The agonist properties of xaliproden at rat and human 5‐HT 1A receptors were determined in vitro by measurement of [ 35 S]GTPγS (guanosine 5'‐O‐(3‐[ 35 S]thio)triphosphate) binding, a measure of G‐proteins activation, on either membranes from rat hippocampus, or from HeLa or glioma C6 cells expressing recombinant human 5‐HT 1A receptors. Complete description of the methodologies, together with relevant literature references are described in Newman‐Tancredi et al. (2007).…”

Section: Methodsmentioning

confidence: 99%

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5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Assié

Bardin

et al. 2009

British J Pharmacology

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Background and purpose: Xaliproden (SR57746A) is a 5-HT1A receptor agonist and neurotrophic agent that reduces oxaliplatin-mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats.Experimental approach: Xaliproden was tested on models associated with 5-HT1A receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT1A receptors was confirmed by antagonism with WAY100635. Key results: Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT1A receptors (pKi = 8.84 and 9.00). In [ , p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED50: 1.2 and 0.7 mg·kg -1 , i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED50: 1 and 3 mg·kg -1 , i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635. Conclusions and implications:These results indicate that activation of 5-HT1A receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT1A receptor activation as an anti-nociceptive strategy. Pharmacology (2009) 158, 232-242; doi:10.1111/j.1476-5381.2009 published online 5 June 2009 This article is part of a themed issue on GPCR. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 is a selective and potent 5-HT1A receptor agonist with low nanomolar affinity at 5-HT1A receptors and an efficacy for activating these receptors equivalent to that of (Ϯ)8-OH-DPAT (Bachy et al., 1993;Cervo et al., 1994). In tests predictive of antidepressant properties, including the forced swim and learned helplessness tests, xaliproden reduced immobility scores and increased the duration of escape ('struggling') behaviour, especially when given in a semi-chronic regimen (Simiand et al., 1993;Cervo et al., 1994). Xaliproden is also active in a number of 'anxiolytic-like' activity tests including a Geller-Seifter conflict test, the staircase and the lithium chloride taste aversion models (Simiand et al., 1993). British Journal ofLater studies of xaliproden focused on pro-neurotrophic properties of this compound in cellular models including rat pheochromocytoma PC12 cells (Pradines et al., 1995;Fournier et al., 1998), primary neuronal cells (Ruigt et al., 1996;Fournier et al., 1998;Magazin et al., 1998;Duong et al., 1999), and in animal models of neurodegeneration (Duong et al., 1998;Iwasaki et al., 1998;Lemaire et al., 2002). These studies suggested that these effects of xaliproden were not due to activation of 5-HT1A receptors because other 5-HT1A agonists [buspirone and (Ϯ)8-OH-DPAT] did not share these pro-neurotrophic properties either in vitro (Pradines et al., 1995) or in vivo . However, more recent data suggest that agonism at 5-HT1A receptors ma...

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“…Competition binding experiments were carried out by using radioligands, buffers and incubation conditions described previously (Newman‐Tancredi et al. , 2007).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Assié

Bardin

et al. 2009

British J Pharmacology

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“…Fourth, the atypical antipsychotic, clozapine, which displays improved capacity to treat negative symptoms with minimal liability for EPS, exhibits agonist properties at 5-HT 1A receptors in various in vitro models of receptor transduction (Assié et al 1997;Bruins Slot et al 2006;Cussac et al 2002;Elliott and Reynolds 1999;Newman-Tancredi et al 2005). The ability of clozapine to occupy 5-HT 1A receptors in nonhuman primates at clinically-relevant doses has been demonstrated by PET scans with [ 3 H]WAY100635 (Chou et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Newman‐Tancredi

Kleven²

2011

Psychopharmacology

146

108

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Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.

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“…Such drugs include aripiprazole, bifeprunox, SSR181507, SLV313, RGH188 and F15063 (Claustre et al, 2003 ;Kiss et al, 2006 ;McCreary et al, 2007 ;Newman-Tancredi et al, 2007 ;Shapiro et al, 2003 ;Wadenberg, 2007). Previous studies have demonstrated that such compounds exhibit varying levels of antagonist or partial agonist properties at D 2 receptors in vitro in measures of G-protein activation at hD 2L receptors (Cosi et al, 2006), phosphorylation of extracellular-regulated kinase (ERK1/2) phosphorylation at hD 2S receptors (Bruins Slot et al, 2006), and activation of G-proteincoupled inwardly rectifying potassium (GIRK) currents in Xenopus oocytes transfected with hD 2L receptors (Heusler et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells

Newman‐Tancredi¹,

Heusler²,

Martel³

et al. 2007

Int. J. Neuropsychopharm.

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Interaction at dopamine D4 receptors may improve cognitive function, which is highly impaired in individuals with schizophrenia, but comparative studies of recent antipsychotics in cellular models of D4 receptor activation are lacking. Here, we report the in-vitro profile of over 30 ligands at recombinant hD4.4 receptors. In [35S]GTPgammaS binding experiments using membranes of CHO-hD4.4 cells, apomorphine, preclamol and the selective D4 agonists, ABT724, CP226269, Ro-10-5824 and PD168077, behaved as partial agonists (Emax 20-60% vs. dopamine), whereas L745870 and RBI257, displayed antagonist properties. The 'conventional' antipsychotic, haloperidol and the 'atypicals', clozapine and risperidone, exhibited antagonist properties, while 'third generation' compounds bifeprunox, SLV313 and F15063, acted as partial agonists (10-30%). Aripiprazole and SSR181507 slightly stimulated [35S]GTPgammaS binding at micromolar concentrations. In Xenopus laevis oocytes co-expressing hD4.4 receptors with G-protein-coupled inwardly rectifying potassium (GIRK) channels, apomorphine, preclamol, ABT724, CP226269, and PD168077 stimulated GIRK currents (Emax 70-80%). The 5-HT1A receptor ligands, WAY100635 and flibanserin, also exhibited partial agonist activity (30% and 15%, respectively). Haloperidol, clozapine, olanzapine and nemonapride did not stimulate GIRK currents, whereas aripiprazole, bifeprunox, SLV313 and F15063, but not SSR181507, exhibited partial agonism (Emax 20-35%). In-vitro responses depended on experimental conditions: increasing NaCl concentration (30 mm to 100 mm) reduced agonist efficacy in [35S]GTPgammaS binding, whereas decreasing the amount of hD4.4 cRNA injected into oocytes (from 2.0 to 0.5 ng/oocyte) reduced agonist efficacy of several compounds. These data indicate that, unlike conventional or 'atypical' antipsychotics, several 'third generation' agents display D4 receptor partial agonism that may be sufficient to influence physiological D4 receptor activity in vivo.

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P.3.d.004 F15063, a novel antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: I. Receptor affinity and efficacy in vitro and activity in neurochemical and neuroendocrine tests in rodents

Cited by 8 publications

References 0 publications

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells

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P.3.d.004 F15063, a novel antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: I. Receptor affinity and efficacy in vitro and activity in neurochemical and neuroendocrine tests in rodents

Cited by 8 publications

References 0 publications

5‐HT1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells

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5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception