Abstract:
BACKGROUND AND PURPOSE:Xaliproden (SR57746A) is a 5-HT(1A) 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-HT(1A) receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT(1A) receptors was confirmed by antagonism with WAY100635. KEY RESULTS:Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT(1A) receptors (pK(i)= 8.84 and 9.00). In [(35)S]GTPgammaS (guanosine 5'-O-(3-[(35)S]thio)triphosphate) assays it activated both hippocampal r5-HT(1A)[pEC(50)/E(MAX) of 7.58/61% (%5-HT)] and recombinant h5-HT(1A) receptors (glioma C6-h5-HT(1A): 7.39/62%; HeLa-h5-HT(1A): 7.24/93%). In functional [(35)S]GTPgammaS autoradiography, xaliproden induced labelling in structures enriched with 5-HT(1A) receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [(3)H]WAY100635 to 5-HT(1A) receptors in mouse frontal cortex and hippocampus (ID(50): 3.5 and 3.3 mg x kg(-1), p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED(50): 1.2 and 0.7 mg x kg(-1), i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED(50): 1 and 3 mg x 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-HT(1A) receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT(1A) receptor activation as an anti-nociceptive strategy.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Martel JC,Assié MB,Bardin L,Depoortère R,Cussac D,Newman-Tancredi Adoi
10.1111/j.1476-5381.2009.00249.xsubject
Has Abstractpub_date
2009-09-01 00:00:00pages
232-42issue
1eissn
0007-1188issn
1476-5381pii
BPH249journal_volume
158pub_type
杂志文章abstract::1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows sinus node rate. Its effects on haemodynamic function have been studied in pentobarbitone anaesthetized dogs, in comparison with zat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17101.x
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1983.tb09359.x
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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pub_type: 杂志文章
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更新日期:2011-02-01 00:00:00