JNJ16259685 robustly and entirely suppresses the increase in intracellular Ca2+ levels triggered by glutamate (30 μM) at the rat mGlu1a receptor, with an IC50 of 3.24±1.00 nM. JNJ16259685 also impedes the glutamate-prompted elevation in intracellular Ca2+ levels at the rat mGlu5a receptor with an IC50 of 1.31±0.39 μM. Moreover, JNJ16259685 obstructs glutamate-induced Ca2+ mobilization at the human mGlu5 receptor with an IC50 of 28.3±11.7 μM. JNJ16259685 does not show any agonist activity at any of the group I mGlu receptors[1].
JNJ16259685 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Purkinje cells
19 nM
10 minutes
To evaluate the inhibitory effect of JNJ16259685 on mGlu1 receptor-mediated EPSP in Purkinje cells, showing that JNJ16259685 inhibits synaptic activation of mGlu1 in a concentration-dependent manner.
Br J Pharmacol. 2007 Jul;151(6):870-6
Rat VTA dopamine neurons
100 nM
10 minutes
JNJ16259685 blocked DHPG-induced depression of IPSCs, indicating the role of mGluR1 in inhibitory synaptic transmission in VTA dopamine neurons.
Neuropsychopharmacology. 2013 Jun;38(7):1308-21
cerebellar nuclear neurons
0.2 μM
10–15 min
To test the effect of mGluR1 antagonist JNJ16259685 on the firing rate of cerebellar nuclear neurons, results showed a significant reduction in the firing rate increase when combined with MPEP
J Neurosci. 2011 Jul 13;31(28):10283-92
JNJ16259685 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C57BL/6J mice and Homer2 knockout mice
Bilateral infusion into the shell subregion of the nucleus accumbens (NAC)
0–30 pg/side
Single injection, alcohol intake assessed over 2 hours
JNJ-16259685 dose-dependently reduced alcohol consumption in C57BL/6J mice, but this effect was absent in Homer2 KO mice.
Neuropharmacology. 2014 Apr;79:679-87
Mice
Eif4ebp2 knock-out mice
Intraperitoneal injection
0.3 mg/kg
Single dose, tested 30 min later
JNJ16259685 reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2 knock-out mice.
J Neurosci. 2015 Aug 5;35(31):11125-32
Rats
Chronic constrictive injury (CCI) model of sciatic nerve
Intraperitoneal injection
5 mg/kg
Once daily for 3 or 7 days
JNJ16259685 prevented thermal hyperalgesia at both 3 and 7 days post-CCI but not mechanical allodynia. Additionally, JNJ16259685 increased the expression of the anti-apoptotic gene bcl-2 and inhibited the over-expression of APAF-1 and caspase-7 genes.
Pharmacol Res. 2008 Mar;57(3):223-33
Nude mice
Melanoma cell xenograft model
Subcutaneous injection
10mg/kg
Five times per week for 22 days
JNJ16259685 significantly decreased the rate of SK2 and SK5 melanoma tumor growth
Oncogene. 2015 May 21;34(21):2711-20
Male Sprague-Dawley rats
Cocaine-induced conditioned place preference (CPP) model
Bilateral intra-VTA microinjection
0.1 ng/side
Injected 30 min prior to each cocaine or saline pairing, for 8 days
JNJ16259685 significantly attenuated cocaine-induced CPP, suggesting that mGluR1-dependent protein synthesis is critically involved in the acquisition of cocaine CPP.
Neuropsychopharmacology. 2013 Jun;38(7):1308-21
Rat
Cerebellar slice model
Systemic administration
IC50 value of 19 nM
Tested the antagonistic effect of JNJ16259685 on synaptic transmission in cerebellar Purkinje neurons, showing high selectivity and potency.
Br J Pharmacol. 2007 Jul;151(6):723-4
Rats
Conditioned place preference model
Intraperitoneal injection
0.3mg/kg
Once daily for two days
To evaluate the effect of JNJ16259685 on the maintenance of methamphetamine-induced conditioned place preference, results showed that JNJ16259685 did not influence the maintenance of methamphetamine-induced CPP.
Eur Neuropsychopharmacol. 2013 Jul;23(7):691-6
Mice
SCA1 82Q mouse model
Subcutaneous injection
0.03 mg/kg
Single dose
JNJ16259685 shortened the prolonged mGluR1 currents and improved moderate ataxia
J Neurosci. 2016 May 4;36(18):4910-6
Rats
Alcohol discrimination training model
Intraperitoneal injection
0.3–3 mg/kg
Single administration
To evaluate the effect of mGlu1 receptor antagonism on the discriminative stimulus effects of alcohol, results showed that JNJ16259685 did not alter the discriminative stimulus effects of alcohol.
J Neurosci. 2009 Jul 29;29(30):9582-91
Mouse
Cerebellar slices
Perfusion
0.2 μM
Single administration, recordings made 10–15 min after perfusion
To test the effect of JNJ16259685 on the firing rate of cerebellar nuclear neurons, results showed a significant reduction in the firing rate increase when combined with MPEP
J Neurosci. 2011 Jul 13;31(28):10283-92
JNJ16259685 动物研究
Animal study
Administered intraperitoneally, JNJ16259685 at doses of 0.25, 0.5, 1, 2, 4, and 8 mg/kg notably diminishes the duration of digging behaviors, as well as threat and attack behaviors, when compared to the vehicle group[2]. At a dosage of 30 mg/kg, JNJ16259685 has a negligible impact on locomotor activity. It significantly decreases rearing behavior, exploration in new environments, and lever pressing for food rewards (in rats at 0.3 mg/kg and in mice at 1 mg/kg). When administered subcutaneously at 30 mg/kg, JNJ16259685 does not affect the reflexive startle responses to loud sounds or foot shocks in mice[3].
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