Ditolylguanidine (1,3-Di-o-tolylguanidine) is an agonist of sigma receptor (σ1/σ2 receptor)[1]. The effects of σ receptor agonists on the Müller cell swelling were abrogated in the presence of blockers of metabotropic glutamate and purinergic P2Y1 receptors, respectively, suggesting that σ receptor activation triggers activation of a glutamatergic-purinergic signaling cascade which is known to prevent the osmotic Müller cell swelling[2].Ditolylguanidine (DTG) is a ligand which binds with high affinity to neuronal sigma receptors. DTG and (+)-SKF10047 (N-allylnormetazocine) produced a concentration-dependent suppression of the depolarization of enteric neurons evoked by ionophoresis of ACh. The EC50 values for DTG and (+)-SKF10047 were 4.7 and 3.8 microM, respectively, and were similar to that for hexamethonium (3.2 microM). DTG and hexamethonium (each at 1 microM) were more effective blockers of ACh-induced inward currents at a holding potential of -100 mV than at -40 mV[3]. DTG totally blocked the female sex hormone-induced inhibition on ET-1 release, whereas testosterone-induced stimulation was not affected[4].
Ditolylguanidine 细胞实验
Cell Line
Concentration
Treated Time
Description
References
rat hippocampal slices
100 nM
inhibited NMDA-evoked [3H]NE release
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3774-8
CA3 dorsal hippocampus pyramidal neurones
1 mM
15 to 20 minutes
To evaluate the effect of DTG on NMDA-induced neuronal activation; in control animals, DTG significantly enhanced the NMDA response, but in PTX-pretreated animals, DTG induced a slight but significant reduction of NMDA-induced neuronal activation.
Br J Pharmacol. 1994 Jun;112(2):709-15
rat hippocampal slices
>100 nM
40 minutes
DTG at concentrations greater than 100 nM inhibited NMDA-evoked [3H]-NA release, with maximal inhibition of 86% at 3 μM.
Br J Pharmacol. 1996 Sep;119(1):65-72
mouse hippocampal neurons
50-300 μM
3 seconds
DTG attenuated NMDA-evoked currents with an IC50 of 37±5 μM, showing minimal effects on kainate- and AMPA-evoked currents.
Br J Pharmacol. 1993 Aug;109(4):1196-205
rat hippocampal neurons
10-100 μM
25 seconds
DTG produced a concentration-dependent depression of NMDA-evoked rises in intracellular free calcium ([Ca2+]i), with lesser effects on kainate- and AMPA-evoked responses.
Br J Pharmacol. 1993 Aug;109(4):1196-205
rat brain membranes
3.4 nM
90 minutes
Investigate the binding sites of DTG in rat brain membranes, results showed DTG interacts with one binding site.
Br J Pharmacol. 1992 Nov;107(3):726-31
guinea-pig brain membranes
3.4 nM
90 minutes
Investigate the binding sites of DTG in guinea-pig brain membranes, results showed DTG interacts with at least two binding sites.
Br J Pharmacol. 1992 Nov;107(3):726-31
rat hippocampal CA1 pyramidal neurons
15 μM
60 minutes
Investigation of Ditolylguanidine's inhibitory effects on Mg2+-free induced epileptiform activity, showing reversible inhibition of evoked epileptiform field potentials with an IC50 of 15 μM.
Br J Pharmacol. 1998 Jul;124(5):917-29
Ditolylguanidine 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Rat nucleus accumbens shell microdialysis model
Intravenous injection
1.0–5.6 mg/kg
Single administration, observation time up to 45 minutes
To evaluate the effects of DTG on dopamine levels in the nucleus accumbens shell, results showed that DTG dose-dependently increased dopamine levels, with the highest dose (5.6 mg/kg) peaking at 10 minutes post-administration, reaching approximately 150% of baseline levels.
Biol Psychiatry. 2011 Feb 1;69(3):208-17
Sprague-Dawley rats
PTX-pretreated rat model
Intravenous injection
1 μg/kg
Single injection
To assess the modulatory effect of DTG on the NMDA response; in PTX-treated rats, DTG neither enhanced nor reduced the NMDA-induced neuronal activation.
Br J Pharmacol. 1994 Jun;112(2):709-15
Mice
Amnesia models induced by CO exposure or trimethyltin intoxication
Subcutaneous injection
0.1 mg/kg
Single administration, 30 minutes before testing
DTG significantly reversed the spontaneous alternation deficits observed in mice after CO exposure or trimethyltin intoxication.
Br J Pharmacol. 1999 May;127(2):335-42
Sprague-Dawley rats
Rat dorsal hippocampus CA3 pyramidal neuron model
Subcutaneous
100–1000 mg/kg/day
21-day treatment, 48-hour washout
Long-term low-dose DTG (100 mg/kg/day) enhances NMDA responses, while high doses (1000 mg/kg/day) suppress this potentiation.
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