CGP 35348

CGP 35348 is a selective antagonist of γ-aminobutyric acidB (GABAB) receptor with IC50 value of 34 μM [1].

The GABAB receptor is a metabotropic transmembrane receptors for GABA that is linked via G-protein to potassium channel. It stimulates the opening of K+ channel and hyperpolarize the neuron.

CGP 35348 is a selective GABAB receptor antagonist that can penetrate the blood-brain barrier. In rat cortex slices, CGP 35348 inhibited the potentiating effect of L-baclofen on adenylate cyclase stimulated by noradrenaline. In the hippocampal slice, CGP 35348 (10, 30, 100 μM) inhibited membrane hyperpolarization induced by L-baclofen (10 μM) and the inhibitory postsynaptic potential [1].

In the spinal cord of the rat, CGP 35348 (3-30 μg) inhibited L-baclofen-induced antinociception in a dose-dependent way [2]. In the rat, CGP 35348 induced pain-like response to mechanical stimulation in a dose-dependent way and reduced the paw withdrawal threshold to pressure [3]. In rats, CGP 35348(500 mg/kg) significantly reduced food consumption by the blockade of central GABAB receptors [4].

References:
[1].  Olpe HR, Karlsson G, Pozza MF, et al. CGP 35348: a centrally active blocker of GABAB receptors. Eur J Pharmacol, 1990, 187(1): 27-38.
[2].  Hammond DL, Washington JD. Antagonism of L-baclofen-induced antinociception by CGP 35348 in the spinal cord of the rat. Eur J Pharmacol, 1993, 234(2-3): 255-262.
[3].  Hao JX, Xu XJ, Wiesenfeld-Hallin Z. Intrathecal gamma-aminobutyric acidB (GABAB) receptor antagonist CGP 35348 induces hypersensitivity to mechanical stimuli in the rat. Neurosci Lett, 1994, 182(2): 299-302.
[4].  Patel SM, Ebenezer IS. The effects of intraperitoneal and intracerebroventricular administration of the GABAB receptor antagonist CGP 35348 on food intake in rats. Eur J Pharmacol, 2004, 503(1-3): 89-93.

Effect of GABAB receptor antagonists (CGP 35348 and CGP 55845) on serum interleukin 6 and 18 concentrations in albino mice following neonatal hypoxia ischemia insult.[Pubmed:27731803]

Pak J Pharm Sci. 2016 Sep;29(5):1503-1508.

Interleukin (IL) 6 and 18 plays an important role in inflammatory response following hypoxia ischemia encephalopathy (HIE). Present study was designed to demonstrate the effect of two GABAB receptor antagonists (CGP 35348 and 55845), respectively, on the serum IL6 and IL 18 concentrations in albino mice. Albino mice pups (of both genders) were subjected to Murine model of hypoxia-ischemia encephalopathy on postnatal day 10 (right common carotid artery was ligated followed by 8% hypoxia for 25 minutes). After neonatal brain damage and following weaning, mice were divided in three groups, in gender specific manner, and fed on normal rodent diet till they were 13 week old. At this time point, group 1 received intraperitonial saline solution (control group), group 2 was supplemented with CGP 35348 (1mg/ml solvent/Kg body weight) and group 3 with CGP 55845 (1mg/ml solvent/Kg body weight), intraperitonially, for 12 days and IL 6 and 18 concentrations were determined in serum by ELISA. It was observed that CGP 35348 supplementation resulted in reduced interlukin-6 and interlukin-18 concentrations in male albino mice. While CGP 55845 supplementation increased IL-6 and IL-18 concentrations in female albino mice following HIE. Our results are indicating that GABAB receptor antagonist's supplementation affects IL concentrations in albino mice in a gender specific manner following neonatal brain damage and can be further explored for the treatments of hypoxia ischemia associated neurological ailments.

CGP 35348, GABA B receptor antagonist, has a potential to improve neuromuscular coordination and spatial learning in albino mouse following neonatal brain damage.[Pubmed:24804211]

Biomed Res Int. 2014;2014:295215.

To study the effect of CGP 35348 on learning and memory in albino mice following hypoxia ischemia insult, 10 days old albino mice were subjected to right common carotid artery ligation followed by 8% hypoxia for 25 minutes. Following brain damage, mice were fed on normal rodent diet till they were 13 week old. At this time point, mice were divided into two groups. Group 1 received saline and group 2 intrapertoneally CGP 35348 (1 mg/mL solvent/Kg body weight) for 12 days. A battery of tests used to assess long term neurofunction (Morris water maze, Rota rod and open field) along with brain infarct measurement. Overall CGP 35348 has improved the motor function in male and female albino mice but effects were more pronounced in female albino mice. In open field, CGP 35348 treated female albino mice had demonstrated poor exploratory behavior. During Morris water maze test, gender specific effects were observed as CGP 35348 had improved spatial learning and memory and swimming speed in male albino mice but had no effect in female albino mice following hypoxia ischemia encephalopathy (HIE). We concluded that GABAB receptor antagonists CGP 35348 can be used to improve gender based spatial memory.

GABA-B receptor antagonist CGP 35348 interferes with an arrest of cortical epileptic afterdischarges in developing rats.[Pubmed:20863662]

Epilepsy Res. 2010 Dec;92(2-3):125-33.

Epileptic seizures activate not only excitatory but also inhibitory systems what results in an arrest of seizures. Our recent data indicate that GABAergic inhibition plays an important role in this process in cortically elicited seizures. We started to study the role of GABA-B receptors in cortical epileptic afterdischarges (ADs) in immature rats 12, 18 and 25 days old with implanted electrodes. Low-frequency stimulation of sensorimotor cortical area was repeated with increasing intensities of stimulation current. Thresholds for movements directly elicited by stimulation, for spike-and-wave type of AD, for clonic seizures accompanying this type of ADs and for transition into limbic type of AD were decreased by the 200mg/kg dose of a GABA-B receptor antagonist CGP35348 in all three age groups. Duration of ADs was markedly increased by 50, 100 as well as 200mg/kg dose of CGP35348. The effects were best expressed in 18-day-old rats. To conclude, GABA-B receptors play an important role in generation and especially in arrest of cortical seizures in immature rats.

The effects of intraperitoneal and intracerebroventricular administration of the GABAB receptor antagonist CGP 35348 on food intake in rats.[Pubmed:15496301]

Eur J Pharmacol. 2004 Oct 25;503(1-3):89-93.

In order to test the hypothesis that endogenous gamma-aminobutyric acid (GABA), acting at central GABAB receptors, plays a physiological role in the control of feeding behaviour, it was reasoned that blocking these receptors with a centrally active GABAB receptor antagonist should reduce food intake in hungry rats. In the present study, experiments were carried out to test this possibility using the GABAB receptor antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid (CGP 35348), which is water-soluble and can penetrate the blood-brain barrier from the systemic circulation. CGP 35348 (50 and 100 mg/kg, i.p.) had no effect on food intake in 22-h fasted rats, but a higher dose (i.e. 500 mg/kg., i.p.) significantly reduced cumulative food consumption. These findings are consistent with previous observations that high systemic doses of CGP 35348 are needed to block central GABAB receptors. However, to eliminate the possibility that the 500 mg/kg dose of CGP 35348 decreased food intake by a peripheral, rather than a central mode of action, further experiments were undertaken where the drug was given directly into the brain by the intracerebroventricular (i.c.v.) route. I.c.v. administration of CGP 35348 (5 and 10 microg) significantly decreased cumulative food intake food intake in rats that had been fasted for 22 h. By contrast, i.c.v. administration of CGP 35348 (10 microg) had no effect on water intake in 16-h water-deprived rats. The results indicate that CGP 35348 reduces food consumption in hungry rats by blocking central GABAB receptors in a behaviourally specific manner. These findings suggest that endogenous GABA acting at central GABAB receptors plays a physiological role in the regulation of feeding behaviour.

GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS.[Pubmed:10341258]

J Neurosci. 1999 Jun 1;19(11):4609-15.

The present experiments used CGP 35348, a selective GABAB receptor antagonist with a significantly higher affinity for post- versus presynaptic receptors, to dissociate the role of antagonist concentration versus stimulation mode in determining whether GABAB receptor blockade facilitates or suppresses long-term potentiation (LTP). The antagonist was applied by pressure ejection to one of two recording sites in area CA1 of hippocampal slices before LTP was induced at both sites with either theta burst or high-frequency stimulation (TBS or HFS). TBS produced a dose-dependent facilitation of potentiation that turned into depression at the highest concentration tested, a result reflecting the dose-dependent balance between the drug's postsynaptic disinhibitory effect and its action on presynaptic autoreceptors regulating the release of GABA. In contrast, HFS-induced LTP increased monotonically with drug concentration, suggesting that blockade of postsynaptic GABAB receptors is the only factor contributing to HFS-induced LTP. To test the relevance of the two sets of LTP results, we performed behavioral studies examining the effect of different dosages of antagonist on spatial retention and found that memory was enhanced at intermediate dosages but not at very low and high concentrations, reminiscent of the bell-shaped dose-response curve obtained for TBS-induced LTP. These findings are consistent with the notion that LTP induced by electrical stimulation modeled after endogenous theta-modulated activity patterns bears more relevance to behavior than does potentiation induced by arbitrary tetanic trains.

Involvement of GABA(B) receptors in convulsant-induced epileptiform activity in rat neocortex in vitro.[Pubmed:9824455]

Eur J Neurosci. 1998 Nov;10(11):3417-27.

The role of gamma-aminobutyric acid B (GABA(B)) receptors in the generation and maintenance of bicuculline-induced epileptiform activity in rat neocortical slices was studied using electrophysiological methods. A block of GABA(B) receptors in the presence of functional GABA(A) receptor-mediated inhibition was not sufficient to induce epileptiform activity. In the presence of the GABA(A) receptor antagonist bicuculline (10 microM) and at suprathreshold stimulation, the GABA(B) receptor antagonist CGP 35348 (10-300 microM) significantly potentiated epileptiform activity. With stimulation at threshold intensity, low concentrations of CGP 35348 (10-30 microM) potentiated bicuculline-induced activity, whereas higher concentrations (100-300 microM) invariably led to a reversible suppression of stimulus-evoked epileptiform discharges. CGP 35348 also enhanced picrotoxin-induced epileptiform activity, but at higher concentrations it was considerably less effective in suppressing such epileptiform discharges. The GABA uptake inhibitor nipecotic acid partially mimicked the actions of CGP 35348: with stimulation at threshold intensity, it reversibly suppressed bicuculline-induced epileptiform field potentials, but it did not influence epileptiform activity induced by picrotoxin. We conclude that a postsynaptic blockade of GABA(B) receptors induces an amplification of epileptiform activity in neocortical slices disinhibited by GABA(A) receptor antagonists. An additional blockade of presynaptic GABA(B) receptors, especially under conditions of weak stimulation of the neurons, reduces the inhibitory auto-feedback control of GABA release, leading to a displacement of competitive antagonists from the postsynaptic GABA(A) receptor and hence, to a suppression of epileptiform activity induced by competitive GABA(A) receptor antagonists.

Intrathecal gamma-aminobutyric acidB (GABAB) receptor antagonist CGP 35348 induces hypersensitivity to mechanical stimuli in the rat.[Pubmed:7715832]

Neurosci Lett. 1994 Dec 5;182(2):299-302.

Intrathecal (i.t.) administration of the gamma-aminobutyric acidB (GABAB) receptor antagonist CGP 35348 in the rat resulted in a dose-dependent pain-like response (vocalization) to innocuous mechanical stimuli and touch/pressure). The effect was maximally evoked by stimulation applied to a dermatome corresponding to the spinal levels of the i.t. injections. The paw withdrawal threshold to pressure was also moderately decreased after i.t. CGP 35348. In contrast, i.t. CGP 35348 had no effect on the hot plate test. It is suggested that the input of low threshold afferents innervating mechanoceptors is tonically inhibited by the GABA system through B-type receptors, and blockade of this system results in mechanical hypersensitivity that is similar to mechanical allodynia (painful response to innocuous stimulation) observed in humans.

CGP 35348: a centrally active blocker of GABAB receptors.[Pubmed:2176979]

Eur J Pharmacol. 1990 Oct 2;187(1):27-38.

The biochemical, electrophysiological and pharmacological properties of the new GABAB receptor blocker CGP 35348 are described. In a variety of receptor binding assays CGP 35348 showed affinity for the GABAB receptor only. CGP 35348 had an IC50 of 34 microM at the GABAB receptor. The compound antagonized (100, 300, 1000 microM) the potentiating effect of L-baclofen on noradrenaline-induced stimulation of adenylate cyclase in rat cortex slices. In electrophysiological studies CGP 35348 (10, 100 microM) antagonized the effect of L-baclofen in the isolated rat spinal cord. In the hippocampal slice preparation CGP 35348 (10, 30, 100 microM) blocked the membrane hyperpolarization induced by D/L-baclofen (10 microM) and the late inhibitory postsynaptic potential. CGP 35348 appeared to be 10-30 times more potent than the GABAB receptor blocker phaclofen. Ionophoretic and behavioural experiments showed that GABAB receptors in the brain were blocked after i.p. administration of CGP 35348. This compound may be of considerable value in elucidating the roles of brain GABAB receptors.