GABAA Receptor Partial Agonists and Antagonists: Structure, Binding Mode, and Pharmacology

Krall, Jacob; Balle, Thomas; Krogsgaard‐Larsen, Niels; Sørensen, Troels E.; Krogsgaard‐Larsen, Povl; Kristiansen, Uffe; Frølund, Bente

doi:10.1016/bs.apha.2014.10.003

Cited by 41 publications

(37 citation statements)

References 56 publications

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“…125 The high degree of GABA-A receptor structure/subtype heterogeneity raises expectations for determining specific structures to target these subtypes. 126, 127–129 Subtype specificity may exhibit different effects upon neuronal inhibition in various systems. 130 …”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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“…As noted above, a high degree of heterogeneity of the GABA-A receptor structure/subtype has been observed, which raises the possibility of defining specific structures targeting these subtypes [242,[248][249][250]. Activation of spinal GABA-A ionophores either directly through agonist activation or by positive allosteric modulators has significant preclinical support for further development as reviewed above with benzodiazepines and neurosteroids.…”

Section: Future Directions For Spinal Gaba-a Agonistsmentioning

confidence: 99%

“…Electrophysiological studies have indeed shown GABA-A receptors to be present on both large and small afferents [239] and such studies have emphasized the potent regulation by benzodiazepines of the excitability of small, nociceptive, primary afferents through their associated GABA-A receptors [240]. There is not enough space here to review the differential distribution of functionally distinct GABA-A receptor phenotypes, but electrophysiological and knockout studies have shown considerable phenotype diversity in the neuraxis [241,242].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…Other important classes of antagonists include sulfated neurosteroids [75] and agents derived from 4-PIOL (5-(4-piperidyl)isoxazol-3-ol) [5]. Of particular interest is DPP-4-PIOL (4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide) that selectively antagonizes tonic over phasic GABAergic currents in the hippocampus, suggesting a degree of substrate speciicity [76].…”

Section: Other Gaba Receptor Antagonistsmentioning

confidence: 99%

“…GABA-inhibitory synapses are widely distributed in the CNS with GABA being released by up to 40% of neurons in many brain regions [4]. Speciic GABA receptor antagonists have been described as "essential tools of physiological and pharmacological elucidation of the diferent types of GABA receptor inhibition" [5].…”

Section: Introductionmentioning

confidence: 99%

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

Hinton¹,

Johnston²

2018

GABA and Glutamate - New Developments in Neurotransmission Research

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Agents that antagonize the action of GABA on ionotropic receptors are widely used to probe the function of this neurotransmiter. Three such agents are in common use: bicuculline, gabazine, and picrotoxinin. These three agents produce convulsions on systemic administration but act in signiicantly diferent ways. Bicuculline is a competitive antagonist of GABA A receptors. Gabazine is also a competitive antagonist of GABA A receptors, interacting with diferent residues on the receptors. Picrotoxinin is a noncompetitive antagonist acting on the chloride channel of GABA A and several other ionotropic CYSloop receptors including glycine, GABA C , and 5-HT 3 receptors. Many other structurally diverse agents are now known to act as GABA receptor antagonists, providing opportunities for the discovery of agents with selectivity for the myriad of ionotropic GABA receptors. TPMPA is a selective antagonist for GABA C receptors, which are insensitive to bicuculline. Like TPMPA, many antagonists of ionotropic GABA receptors are not convulsants, indicating that there is still much to be learnt about GABA function in the brain from the study of such agents and their possible therapeutic uses. The most recently discovered GABA A receptor nonconvulsive antagonist is S44819, which is subtype selective for α5-containing receptors, and is arousing much interest in relation to cognition.

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GABAA Receptor Partial Agonists and Antagonists: Structure, Binding Mode, and Pharmacology

Cited by 41 publications

References 56 publications

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Current and Future Issues in the development of spinal agents for the management of pain

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

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