[3H](−)Baclofen: an improved ligand for GABAB sites

doi:10.1016/0028-3908(85)90075-9

Neuropharmacology

Volume 24, Issue 3, March 1985, Pages 207-210

https://doi.org/10.1016/0028-3908(85)90075-9 Get rights and content

Abstract

[³H](−)Baclofen, the radiolabelled form of the active isomer of baclofen, has been used as a ligand for GABA_B (γ-aminobutyric acid) receptors on synaptic membranes from whole brain of rat. The pharmacological profile for displacement of this ligand was observed to be identical with that for the racemic ligand [³H](±)baclofen and [³H]GABA under conditions where GABA_B, but not GABA_A sites, were labelled. The displaceable (specific) portion of membrane-bound [³H](−)baclofen was 47.5 ± 2.3% of the total which was twice that obtained previously with [³H](±)baclofen. Two binding components were observed with affinities of 19 and 304 nM and binding capacities of 0.37 and 1.58 $pmol mg$ protein respectively. It is suggested that [³H](−)baclofen is an improvement over the labelled racemic form and binds to the same sites. It should provide a more reliable tool for studying GABA_B receptors.

References (14)

N.G. Bowery et al.
Bicuculline-insensitive GABA receptors on peripheral autonomic nerve terminals
Eur. J. Pharmac.
(1981)
N.G. Bowery et al.
Evidence that SL75102 is an agonist at GABA_B as well as GABA_A receptors
Neuropharmacology
(1982)
K. Kato et al.
Regulation by divalent cations of ³H-baclofen binding of GABA_B sites in rat cerebellar membranes
Life Sci.
(1983)
N.G. Bowery et al.
Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes
Br. J. Pharmac.
(1983)
A. Giotti et al.
Homotaurine: a GABA_B antagonist in guinea-pig ileum
Br. J. Pharmac.
(1983)
E.G. Gray et al.
The isolation of nerve endings from brain: an electron microscopic study of cell fragments derived from homogenization and centrifugation
J. Anat.
(1962)
A.A. Hancock et al.
Quantitative resolution of beta-adrenergic subtypes of selective ligand binding: application of a computerized model fitting technique
Molec. Pharmac.
(1979)

There are more references available in the full text version of this article.

Cited by (71)

Phenibut exposures and clinical effects reported to a regional poison center
2019, American Journal of Emergency Medicine
Citation Excerpt :
There are numerous xenobiotics with a similar chemical structure, which could explain the diverse clinical effects of phenibut. It is a synthetically produced compound that is structurally similar to GABA and produces clinical effects associated with other GABA agonists in addition to inhibition of the α2δ subunit of VDCC [1,2,12-17]. A considerable percentage (48%) of patients were consuming phenibut for its abuse potential.
Phenibut is a synthetically produced central nervous system (CNS) depressant that is structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Phenibut has been identified as a drug of abuse with numerous clinical effects in overdose and a withdrawal syndrome with chronic use. The purpose of this study is to report the incidence of exposure calls regarding phenibut to a poison center, describe the reasons for its use and clinical effects.
Study subjects were identified using Toxicall®, the electronic medical record utilized by the Minnesota Poison Control System. All phenibut exposure calls from January 2000 through December 2018 were included. Analysis was performed on incidence of exposure calls, reported reasons for use, signs and symptoms, coingestants, and outcome.
There were 56 exposure calls over 19 years with 48 (85.7%) calls within the past five years. Over 50% of patients had CNS effects and 10.7% had withdrawal concerns. Twenty-seven patients (48%) had abuse as the reason for use and 13 (23%) used phenibut to treat anxiety. There were documented coingestants in 35.7% of patients. No patients died due to reported phenibut use, though 11 patients (19.6%) were intubated.
Exposure calls to a regional poison center regarding phenibut have increased over the past five years. CNS depression was common, and associated with significant clinical outcomes including respiratory failure requiring intubation. As phenibut is easily attainable and exposures appear to be increasing, physicians should be aware of phenibut-associated CNS and respiratory depression and be prepared to manage airways appropriately.
GABA <inf>B</inf> receptors in reward processes
2010, Advances in Pharmacology
Citation Excerpt :
Baclofen also attenuated the d-amphetamine-induced increases in dopamine efflux in the NAc (Brebner et al., 2005). Administration of either of two GABAB receptor agonists, CGP44532 or baclofen (Bowery et al., 1985; Froestl et al., 1995a), decreased intravenous nicotine self-administration (Corrigall et al., 2000; Fattore et al., 2002; Paterson et al., 2004). Specifically, baclofen administration prevented acute nicotine self-administration in drug-naive mice (Fattore et al., 2002).
γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain which acts through different receptor subtypes. Metabotropic GABA_B receptors are widely distributed throughout the brain. Alterations in GABA signaling through pharmacological activation or deactivation of the GABA_B receptor regulate behavior and brain reward processes. GABA_B receptor agonists and, most recently, positive modulators have been found to inhibit the reinforcing effects of drugs of abuse, such as cocaine, amphetamine, nicotine, ethanol, and opiates. This converging evidence of the effects of GABA_B compounds on the reinforcing properties of addictive drugs is based on behavioral studies that used a variety of procedures with relevance to reward processes and drug abuse liability, including intracranial self-stimulation, intravenous self-administration under both fixed- and progressive-ratio schedules of reinforcement, reinstatement, and conditioned place preference. GABA_B receptor agonists and positive modulators block the reinforcing effects of drugs of abuse in these animal models. However, GABA_B receptor agonists also have undesirable side-effects. GABA_B receptor modulators have potential advantages as medications for drug addiction. These compounds have a better side-effect profile than GABA_B agonists because they are devoid of intrinsic agonistic activity in the absence of GABA. They only exert their modulatory actions in concert with endogenous GABAergic activity. Thus, GABA_B receptor positive modulators are promising therapeutics for the treatment of various aspects of dependence (e.g., initiation, maintenance, and relapse) on various drugs of abuse, such as cocaine, nicotine, heroin, and alcohol.
Comparative pharmacological activity of optical isomers of phenibut
2008, European Journal of Pharmacology
Phenibut (3-phenyl-4-aminobutyric acid) is a GABA (γ-aminobutyric acid)-mimetic psychotropic drug which is clinically used in its racemic form. The aim of the present study was to compare the effects of racemic phenibut and its optical isomers in pharmacological tests and GABA_B receptor binding studies. In pharmacological tests of locomotor activity, antidepressant and pain effects, S-phenibut was inactive in doses up to 500 mg/kg. In contrast, R-phenibut turned out to be two times more potent than racemic phenibut in most of the tests. In the forced swimming test, at a dose of 100 mg/kg only R-phenibut significantly decreased immobility time. Both R-phenibut and racemic phenibut showed analgesic activity in the tail-flick test with R-phenibut being slightly more active. An GABA_B receptor-selective antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348) inhibited the antidepressant and antinociceptive effects of R-phenibut, as well as locomotor depressing activity of R-phenibut in open field test in vivo. The radioligand binding experiments using a selective GABA_B receptor antagonist [³H]CGP54626 revealed that affinity constants for racemic phenibut, R-phenibut and reference GABA-mimetic baclofen were 177 ± 2, 92 ± 3, 6.0 ± 1 μM, respectively. We conclude that the pharmacological activity of racemic phenibut relies on R-phenibut and this correlates to the binding affinity of enantiomers of phenibut to the GABA_B receptor.
Dual effect of GABA on descending monosynaptic excitatory postsynaptic potential in frog lumbar motoneurons
2004, Neuroscience
Citation Excerpt :
Like in (−)-baclofen experiments, we examined the effect of GABA on VLC EPSP in the presence of GABAB receptor antagonist saclofen. Since (−)-baclofen and GABA are targeted to the same binding site of the GABAB receptor (Bowery et al., 1980, 1985), we were expecting a weaker effect of GABA on the VLC EPSP in the presence of saclofen. Indeed, in five experiments with GABA application in the presence of saclofen the inhibition of conventional VLC EPSP by GABA was partially blocked (17±5.1% reduction, n=5, P<0.05 compared with the control recording, Student's paired t-test; P<0.05 compared with the effect induced by GABA, Student's unpaired-t test Fig. 3B1, B2).
Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulating ipsilateral ventrolateral column (VLC) in the thoracic section were recorded in lumbar motoneurons within the isolated spinal cord of the frog Rana ridibunda. Bath application of the selective GABA_B receptor agonist (−)-baclofen (0.05 mM) caused a reduction in the peak amplitude of VLC EPSP. Baclofen did not cause any consistent change in the membrane potential or in the EPSP waveform within frog motoneurones. The selective GABA_B receptor antagonist saclofen (0.1 mM) completely blocked the effect of (−)-baclofen on VLC EPSP. A decrease in VLC EPSP peak amplitude was also observed during GABA (0.5 mM) application. Unlike (−)-baclofen, inhibition of VLC EPSP induced by GABA was accompanied by a shortening of the EPSP time course and a reduction in membrane input resistance within lumbar motoneurons. The decrease in VLC EPSP peak amplitude induced by (−)-baclofen and GABA was accompanied by an increase in the paired-pulse facilitation. These data provide evidence for a dual pre- and postsynaptic GABAergic inhibition of the VLC monosynaptic EPSP in lumbar motoneurons within the frog spinal cord.
Twenty years of intrathecal baclofen therapy in Slovenia: A retrospective single-center analysis of complications
2023, International Journal of Rehabilitation Research
The Influence of Pantogam and Atomoxetine on Attention Stability and Distribution of Dopamine D<inf>2</inf> and GABA<inf>B</inf> Receptors in the Attention Deficit Mouse Model
2022, Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry

View all citing articles on Scopus

View full text

[3H](−)Baclofen: an improved ligand for GABAB sites

Abstract

Eur. J. Pharmac.

Neuropharmacology

Life Sci.

Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes

Br. J. Pharmac.

Homotaurine: a GABAB antagonist in guinea-pig ileum

Br. J. Pharmac.

The isolation of nerve endings from brain: an electron microscopic study of cell fragments derived from homogenization and centrifugation

J. Anat.

Quantitative resolution of beta-adrenergic subtypes of selective ligand binding: application of a computerized model fitting technique

Molec. Pharmac.

[³H](−)Baclofen: an improved ligand for GABA_B sites

Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes

Homotaurine: a GABA_B antagonist in guinea-pig ileum