Arylalkylamines are a novel class of positive allosteric modulators at GABAB receptors in rat neocortex

Kerr, Donald; Ong, Jennifer; Puspawati, Ni Made; Prager, R. H.

doi:10.1016/s0014-2999(02)02195-7

Cited by 36 publications

(31 citation statements)

References 15 publications

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“…Three arylalkylamine derivatives have meanwhile also been reported to enhance GABA B receptor-mediated responses in rat cortical slices (Kerr et al, 2002). However, in that report molecular mechanisms of action were not addressed.…”

Section: Discussionmentioning

confidence: 98%

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

Urwyler¹,

Pozza²,

Lingenhoehl³

et al. 2003

J Pharmacol Exp Ther

182

160

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N, increases agonist affinities. Agonist displacement curves are biphasic, probably reflecting the G protein-coupled and uncoupled states of the receptor. The proportion of the high-affinity component is increased by GS39783, suggesting that the G protein coupling of the receptor is also promoted by the positive modulator. We also show that GS39783 has modulatory effects in cellular assays such as GABA B receptor-mediated activation of inwardly rectifying potassium channels in Xenopus oocytes and Ca 2ϩ signaling in human embryonic kidney 293 cells. In a more physiological context, GS39783 is shown to suppress paired pulse inhibition in rat hippocampal slices. This effect is reversed by the competitive GABA B receptor antagonist CGP55845A and is produced most likely by enhancing the effect of synaptically released GABA at presynaptic GABA B receptors.The receptors for the major inhibitory neurotransmitter in the central nervous system, GABA, are subdivided into ionotropic GABA A receptors and metabotropic GABA B receptors. Whereas GABA A receptors form a chloride-permeable ion channel that elicits short-lasting inhibitory postsynaptic potentials, GABA B receptors are G-protein coupled receptors (GPCRs) that inhibit cyclic AMP formation and modulate the activity of inwardly rectifying potassium channels and voltage-sensitive calcium channels. By these mechanisms, they act post-and presynaptically to inhibit neuronal excitability (by producing a late, long-lasting component of inhibitory postsynaptic potentials) and neurotransmitter release, respectively. Whereas benzodiazepines are well established positive allosteric modulators of GABA A receptor function, the first examples of such allosteric enhancers for GABA B receptors have only recently been described (Urwyler et al., 2001). As a therapeutic principle, positive modulators are expected to have several advantages over compounds acting as agonists, because they are only effective in the presence of the endogenous ligand and therefore act in line with physiological neurotransmission in its temporal and spatial organization. Agonists, on the other hand, activate receptors independently of synaptic activity, possibly leading to unwanted side effects. For these reasons, the search for posArticle, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 98%

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

Urwyler¹,

Pozza²,

Lingenhoehl³

et al. 2003

J Pharmacol Exp Ther

182

160

View full text Add to dashboard Cite

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“…Notably the repertoire of GABA B compounds was expanded to include positive allosteric modulators (175,263,330,331). Chances are that positive allosteric compounds will be therapeutically effective, since a basal GABA B activity is present in many diseaserelevant neuronal pathways (272,300).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Kerr et al (175) described the arylalkylamines as a different class of positive allosteric GABA B modulators. Fendiline, prenylamine, and F551 potentiated hyperpolarizing responses to baclofen in rat cortical slices.…”

Section: A Allosteric Modulatorsmentioning

confidence: 99%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

798

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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“…This has prompted Kerr et al (2002) and Kerr and Ong (2003) to examine several arylalkylamines, amino acids, and dipeptides for their actions on GABA B receptor-mediated responses. They found that these agents enhanced baclofen-induced field potentials in rat neocortical slices.…”

Section: E Modulation Of Gaba B Receptor Function By Other Mechanismmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Arylalkylamines are a novel class of positive allosteric modulators at GABAB receptors in rat neocortex

Cited by 36 publications

References 15 publications

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

Molecular Structure and Physiological Functions of GABA_BReceptors

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

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Arylalkylamines are a novel class of positive allosteric modulators at GABAB receptors in rat neocortex

Cited by 36 publications

References 15 publications

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric AcidB Receptor Function

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric AcidB Receptor Function

Molecular Structure and Physiological Functions of GABABReceptors

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Contact Info

Product

Resources

About

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid_B Receptor Function

Molecular Structure and Physiological Functions of GABA_BReceptors