Xaliproden (hydrochloride)

Xaliproden (SR57746) hydrochloride (SR57746A) is an orally active, highly selective 5-HT1A receptor agonist. Xaliproden hydrochloride activates pertussis toxin-sensitive G protein-coupled signaling cascades, as well as the PKC, ERK1/ERK2, Akt and p21 Ras/MEK-1 pathways. Xaliproden hydrochloride also downregulates the JNK/p66/c-Jun signaling pathway, induces phosphorylation of the shc adaptor protein, regulates extracellular dopamine and 5-HT levels, and induces [³⁵S]GTPγS labeling in rat brain structures rich in 5-HT1A receptors. Xaliproden hydrochloride exerts neurotrophic, neuroprotective, renoprotective, anti-inflammatory, anti-apoptotic, anti-fibrotic and analgesic effects. Xaliproden hydrochloride also enhances NGF-induced neurite outgrowth, promotes motor neuron survival, attenuates renal tubular injury and inhibits chemotherapy-induced mechanical allodynia, without activating or altering NGF-induced TrkA receptor activation. Xaliproden hydrochloride can be used in the research of motor neuron disease, diabetic nephropathy, chemotherapy-induced peripheral neuropathy, amyotrophic lateral sclerosis, Alzheimer's disease, acute tonic nociceptive pain, inflammatory pain, depression and anxiety^[1][2][3][4]. In Vitro:Xaliproden hydrochloride (1-10 μM; 5-30 min) does not activate the TrkA receptor in rat pheochromocytoma PC12 cells^[1].
Xaliproden hydrochloride (1 μM; 5 min-48 h) induces time-dependent tyrosine phosphorylation of the p66^shc and p52^shc isoforms in rat pheochromocytoma PC12 cells, with the phosphorylation of p66^shc peaking at 5 min and that of p52^shc peaking at 48 h^[1].
Xaliproden hydrochloride (0.1-5 μM; 5-30 min) induces dose-dependent transient activation of ERK1/ERK2 MAP kinases in PC12 rat pheochromocytoma cells, with a 3-fold activation peak of ERK2 at 1 μM for 5 min, and the maximum activation level achieved at 5 μM for 5 min^[1].
Activation of ERK1/ERK2 MAP kinases and phosphorylation of PKC isoforms induced by xaliproden hydrochloride (1 μM; 5-30 min) in PC12 rat pheochromocytoma cells depend on PKC activity, whereas 5-HT_1A receptor antagonism or G_i/o protein inactivation inhibits PKC activation^[1].
Xaliproden hydrochloride (1-10 μM; 24 h) protects human renal proximal tubular epithelial cells from high glucose-induced injury by inhibiting the JNK/p65/c-Jun signaling pathway and alleviating inflammation, apoptosis and fibrosis^[2].
Xaliproden hydrochloride (10 μM) activates G proteins via native 5-HT_1a receptors in the rat hippocampus, lateral septum, frontal cortex and entorhinal cortex, and this effect is completely blocked by the 5-HT_1a receptor antagonist WAY100635 (HY-10349)^[4]. In Vivo:Xaliproden extends the average survival time and improves motor function in pmn mice with hereditary axonopathy, and rescues motor neurons from death in mice with transected sciatic nerves^[1].
Xaliproden (0.3-1.5 mg/kg/day; oral administration; once daily; for 4 consecutive weeks) hydrochloride exerts renoprotective effects on db/db mice with diabetic nephropathy by significantly improving renal function, reducing proteinuria, alleviating renal tubular injury and fibrosis, as well as blocking inflammatory, apoptotic and fibrotic pathways via inhibition of the JNK/p65/c-Jun signaling axis^[2].
Xaliproden (0.3-3 mg/kg; p.o.; single administration) hydrochloride significantly, persistently and dose-dependently inhibits Paclitaxel (HY-B0015)-induced mechanical allodynia^[3].
Xaliproden (0.3-3 mg/kg; p.o.; single administration) hydrochloride exerts only a mild, transient 19% inhibition of vincristine (HY-N0488A)-induced mechanical allodynia at the single dose of 3 mg/kg, shows no effect at low doses, and does not alter the tibial nerve firing response in vincristine-treated mice^[3].
Xaliproden (0.63-40 mg/kg; p.o.; single administration) hydrochloride produces a dose-dependent inhibitory effect on in vivo 5-HT_1A receptor binding in the frontal cortex and hippocampus of mice, with ID₅₀ values of 3.5 mg/kg and 3.3 mg/kg (p.o.), respectively^[4].
Xaliproden (0.63-10 mg/kg; intraperitoneal injection; single administration) hydrochloride dose-dependently increases dopamine levels in the prefrontal cortex of rats (ED₅₀=0.7 mg/kg, i.p.) and decreases 5-HT levels in the rat hippocampus (ED₅₀=1.2 mg/kg, i.p.) via activation of the 5-HT_1A receptor^[4].
Xaliproden (0.63-10 mg/kg; intraperitoneal injection; single administration) hydrochloride exerts a dose-dependent, 5-HT_1A receptor-mediated antinociceptive effect in the rat formalin pain test, and completely inhibits paw licking and lifting responses at 10 mg/kg (i.p.)^[4].