GABAB receptor: a site of therapeutic benefit

doi:10.1016/j.coph.2005.10.002

Current Opinion in Pharmacology

Volume 6, Issue 1, February 2006, Pages 37-43

https://doi.org/10.1016/j.coph.2005.10.002 Get rights and content

Although the presence of functional GABA_B receptors in mammalian brain has been known for more than 20 years, there is still only one therapeutic agent in use, baclofen, which mediates its effects directly via this receptor. However, activation of this receptor can produce numerous effects that might be amenable to drug development. Evidence from preclinical studies also suggests that antagonism of the GABA_B receptor produces beneficial clinical effects.

Introduction

Metabotropic receptors provide the site of action for the majority of therapeutic agents currently in clinical use. However, there are many receptors in this class that have yet to be therapeutically exploited, among which is the GABA_B receptor. The natural ligand for this receptor is the amino acid γ-amino-butyric acid (GABA), which is well established as the primary inhibitory transmitter acting at ionotropic GABA_A receptors. Many centrally acting drugs mediate their effect(s) by facilitation of GABA_A receptor mechanisms, including the benzodiazepines. By contrast, only one compound in current clinical use — baclofen (β p-chlorophenyl-GABA; Figure 1) — is known to mediate its effects directly through activation of the GABA_B site. However, substances that increase the extracellular levels of GABA might also produce effects on GABA_B sites mediated indirectly by endogenous GABA. Baclofen, which is used to reduce the symptoms of spasticity, was introduced into therapeutic use in 1972 [1, 2], well before the existence of GABA_B receptors was recognized and, like so many of the older centrally active agents, its introduction into medicine was not accompanied by a defined mechanism of action, although it was designed as a GABA mimetic. Fortunately, it was screened for muscle relaxant activity using an in vivo technique. Had the compound been screened specifically for ionotropic actions by existing in vitro assays, its effects might have been missed.

The structure of the GABA_B receptor was fully identified in 1998 [3, 4, 5] when it was shown to exist as a heterodimer with two subunits, GABA_B1 and GABA_B2, which provide different functions but are mutually dependent (for review, see [6]). The former contains the GABA-binding domain, whereas GABA_B2 provides the G-protein-coupling mechanism and also incorporates an allosteric modulatory site within its heptahelical structure [7, 8, 9•]. Although different functional isoforms of GABA_B1 have been defined, there is, as yet, no unequivocal evidence for distinct GABA_B receptor subtypes. The receptors are located in the brain both pre- and post-synaptically where they are coupled to Ca²⁺ and K⁺ channels. Therefore, when receptor activation occurs, a variety of effects might be expected to occur as a consequence of inhibition of transmitter release and/or neuronal hyperpolarisation. Having a selective agonist for the receptor, together with information derived from ‘knockout’ mice (Table 1), has provided the basis for much of the speculation about the potential therapeutic benefits of both agonists and antagonists for the GABA_B receptor.

A list of the in vitro and in vivo actions of baclofen is shown in Table 2; predominant among these are the muscle relaxant, anti-nociceptive and anti-drug craving effects, as well as the reduction in cognitive behaviour.

Section snippets

Spasticity

The centrally mediated muscle-relaxant properties of baclofen are well established clinically, making it the drug of choice in spasticity associated with cerebral palsy, multiple sclerosis, stiff-man syndrome and tetanus. However, the side effects produced by this drug (Table 2) are frequently not tolerated by patients because of the need to administer high doses of the agonist owing to poor brain penetration. This has been largely overcome by the introduction of intrathecal administration

Pain

An analgesic/antinociceptive action of baclofen administered systemically was first described more than 25 years ago and subsequently confirmed by many different groups; however, rapid tolerance to the effects was also noted. If the drug was given intrathecally to suppress central pain in humans, no tolerance was reported. The mechanism underlying this antinociceptive action within the spinal cord appears to derive from suppression of the release of primary afferent transmitter [12, 13, 14].

Cognition

The ability of baclofen to suppress cognitive behaviour in animals is well documented (e.g. see [20]). In general, the effects of baclofen on cognition are comparable to those produced by the muscarinic antagonist scopolamine; however, GABA_B-receptor-mediated cognitive impairment is reversed by GABA_B antagonists, whereas that produced by scopolamine is not. Although the effect of baclofen is, of course, of little consequence to clinical medicine, there is the possibility that GABA_B receptor

Drug addiction

Adequate therapeutic treatment of dependence on drugs of abuse is still a major clinical target but GABA_B receptor activation could offer a suitable approach. Baclofen was first shown in 1997 [24] to reduce the reinforcing effects of cocaine in rats at doses that do not affect locomotion. It soon became clear that other drugs of addiction, including nicotine, morphine-related agents and ethanol, were also sensitive to GABA_B receptor agonists, whereas food reinforcement was not affected. Indeed,

Depression and anxiety

A connection between GABA_B receptors and the action of antidepressants was first proposed more than 20 years ago by Lloyd et al. [34]. These authors demonstrated that an upregulation in GABA_B binding sites occurs in rat frontal cortex after chronic administration of a variety of antidepressant drugs, as well as after electroconvulsive therapy. Even though these findings were disputed [35, 36], there now seems little doubt that GABA_B receptor mechanisms can be affected in depression [37].

Absence epilepsy

The occurrence of absence seizures is primarily associated with juveniles and frequently disappears during the late teens; however, it can be retained into later years. The characteristic electroencephalogram activity of a 3 Hz spike and wave that is manifest during an absence attack stems from discharges in the thalamic nuclei. It was thought for many years that the thalamus was the site from which these discharges originate; however, although an intact thalamocortical network is necessary for

Conclusions

The full therapeutic benefits of GABA_B receptor ligands have yet to be realised even though the existence of the receptor has been known for over 25 years. So one might ask, why? Is it because of the lack of brain-penetrating selective agonists or the lack of effective antagonists? Perhaps the former is true but surely not the latter, as there are now numerous antagonists with sub-nanomolar affinity. However, the one antagonist currently in clinical trials — CGP 36742 (SGS 742) [22^•] — only has

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

Thanks to Dr Stefano Tacconi for preparing Figure 2.

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GABAB receptor: a site of therapeutic benefit

Introduction

Section snippets

Spasticity

Pain

Cognition

Drug addiction

Depression and anxiety

Absence epilepsy

Conclusions

References and recommended reading

Acknowledgements

J Biol Chem

Neuroscience

Neuroscience

Eur J Pharmacol

Stereotact Funct Neurosurg

Neuropharmacology

Biochem Pharmacol

Br J Pharmacol

J Neurosci Res

Psychopharmacology (Berl)

Eur J Pharmacol

Arch Neurol

Trends Pharmacol Sci

Neuron

Pharmacological differentiations of muscle relaxants

Synthesis and structure-activity relationship of the gamma-aminobutyric acid derivatives

GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2

Nature

GABAB receptor subtypes assemble into functional heteromeric complexes

Nature

Heterodimerization is required for the formation of a functional GABAB receptor

Nature

International Union of Pharmacology. XXXIII. Mammalian γ-aminobutyric acidB receptors: structure and function

Pharmacol Rev

The GABAB2 subunit is essential for G protein coupling of the GABAB receptor heterodimer

J Neurosci

The characterization of GABA binding site in GABABR1 receptor shed some light functioning of the heteromeric GABAB receptor

Eur J Neurosci

Intrathecal baclofen for severe spinal spasticity

N Engl J Med

GABA_B receptor: a site of therapeutic benefit

GABA_B receptors function as a heteromeric assembly of the subunits GABA_BR1 and GABA_BR2

GABA_B receptor subtypes assemble into functional heteromeric complexes

Heterodimerization is required for the formation of a functional GABA_B receptor

International Union of Pharmacology. XXXIII. Mammalian γ-aminobutyric acid_B receptors: structure and function

The GABA_B2 subunit is essential for G protein coupling of the GABA_B receptor heterodimer

The characterization of GABA binding site in GABA_BR1 receptor shed some light functioning of the heteromeric GABA_B receptor