GPR39 is a putative zinc-sensing G protein-coupled receptor (GPCR) related to the ghrelin/neurotensin peptide receptor subfamily which is implicated in cellular processes such as insulin secretion, protection from cell death, gastric emptying, and epithelial repair. GPR39-C3 is a potent and oral active GPR39 agonist with EC50s of 0.4 and 0.8 nM for rat and human receptors, respectively[1]. As a GPR39 positive allosteric modulator, GPR39-C3 activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment in HEK293-GPR39 cells. Moreover, GPR39-C3 induced dose- and time-dependent loss of response in cAMP production by second challenge of the compound[2]. In vivo, GPR39-C3 (30 mg/kg po) robustly induced acute GLP-1 levels in mice which is a PD marker[1].
TC-G-1008 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice (Swiss Albino and C57BL/6/Tar × CBA/Tar)
PTZ-induced kindling model of epilepsy
Intraperitoneal injection
10 mg/kg
Once daily on alternate days during weekdays for 19 injections (Swiss Albino) or 14 injections (C57BL/6/Tar × CBA/Tar)
TC-G 1008 facilitated PTZ-epileptogenesis by acting selectively at GPR39 but markedly increased the activation of CREB in the hippocampus of GPR39 KO mice, suggesting non-selectivity
Cell Mol Life Sci. 2023 Apr 25;80(5):133
CD-1 male mice
Forced swim test (FST)
Intraperitoneally
10 or 15 mg/kg
Single or chronic administration
TC-G 1008 at a dose of 15 mg/kg significantly decreased immobility time in the forced swim test, indicating an antidepressant-like effect.
Pharmacol Rep. 2023 Jun;75(3):609-622
Female Wistar rats
Corticosterone-induced depression and overactive bladder model
Intraperitoneal injection
15 mg/kg/day
Once daily for 7 days
TC-G 1008 alleviated corticosterone-induced depression-like behavior and overactive bladder symptoms, restoring biochemical and cystometric markers to normal levels.
Int J Mol Sci. 2024 Nov 25;25(23):12630
Mice
Epilepsy models
Intraperitoneal injection
2.5, 5, 10, 20, 40 mg/kg
30 min pretreatment
TC-G 1008 decreased the seizure threshold in the MEST test, while it increased the seizure threshold in the 6-hertz-induced seizure threshold test. In the PTZ kindling model, TC-G 1008 aggravated epileptogenesis.
Cells. 2022 Jun 21;11(13):1987
Sprague Dawley rats
Neonatal hypoxic-ischemic encephalopathy (HIE) model
Intranasal administration
5 mg/kg, 15 mg/kg, 45 mg/kg
Administered at 1 h, 25 h, 49 h, and 73 h post-HIE induction
TC-G 1008 attenuated neuroinflammation via the SIRT1/PGC-1α/Nrf2 pathway, improving short-term and long-term neurological deficits
J Neuroinflammation. 2021 Oct 13;18(1):226
Male Swiss Albino mice
Maximal electroshock seizure threshold (MEST) test and pentylenetetrazole (PTZ)-kindling model of epilepsy
Intraperitoneal injection
5, 10, 20 mg/kg
Single administration (MEST test) or repeated administration (PTZ-kindling model, every alternate day for 13 injections)
TC-G-1008 decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. In the PTZ-kindling model, TC-G-1008 increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet.
Cells. 2023 Jan 9;12(2):264
Sprague-Dawley rats
Spared nerve injury-induced neuropathic pain model
Intrathecal injection
5, 20, or 50 μg
Single injection or continuous injection for 5 days
TC-G 1008 significantly alleviated mechanical allodynia in rats with spared nerve injury, improved spinal cord mitochondrial biogenesis, and alleviated neuroinflammation.
Neural Regen Res. 2024 Mar;19(3):687-696
Mice
Traumatic stress-enhanced drinking model
Intraperitoneal injection
5, 7.5, 10 mg/kg
30 min pretreatment time
TC-G significantly suppressed binge drinking in male and female mice in the control studies, but female mice were insensitive to TC-G in the traumatic stress drinking model.
Alcohol Clin Exp Res (Hoboken). 2025 Apr;49(4):866-882
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