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

Abstract

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...

Fenfluramine acts as a positive modulator of sigma-1 receptors

“…In vitro cellular and nuclear functional assays were conducted by Eurofins Cerep (Celle l'Evescault, France), using published methods [16][17][18][19][20][21]. Agonist and antagonist activities were assessed using human recombinant receptors expressed in HEK-293 cells (β 1 adrenergic receptors [ARs] and 5-HT 1A receptors), SK-N-MC cells (β 3 ARs), or Chinese hamster ovary (CHO) cells (M 1 muscarinic acetylcholine receptors [M 1 mAChRs] and β 2 ARs), with 3 × 10 −9 to 1 × 10 −5 M fenfluramine or norfenfluramine.…”

Differences in the Receptor Binding Profile of Lofexidine Compared to Clonidine

“…Vectors containing the receptors were transfected into HEK293 (human embryonic kidney 293) cells, and the assays were conducted according to methods previously published [13]- [19].…”

New Arylpiperazinylalkyl Derivatives of 8‐Alkoxy‐purine‐2,6‐dione and Dihydro[1,3]oxazolo[2,3‐f]purinedione Targeting the Serotonin 5‐HT1A/5‐HT2A/5‐HT7 and Dopamine D2 Receptors

“…The preliminary functional activity of the selected compounds 15 and 16 on evaluated Rs, on intracellular cAMP levels, was determined at Cerep (Le Bois l'Eveque, 86600 Celle L'Evescault, France) according to the previously published methods [26][27][28][29][30]. The assays were carried out in HEK-293 and CHO cells which stably express human 5-HT 1A , 5-HT 2A , 5-HT 7 , and D 2 Rs, respectively, with WAY 10063, ketanserin, methiothepin, and butaclamol (antagonistic effect) and 8-OH-DPAT, and 5-HT (agonistic effect) as reference compounds.…”