GABRB2 modulators(gamma-aminobutyric acid type A receptor subunit beta2 modulators), GABRB3 modulators(gamma-aminobutyric acid type A receptor subunit beta3 modulators)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Neuralgia

Originator Organization

University of California, Irvine Extension

Active Organization-

Inactive Organization

University of Arizona

University of California, Irvine Extension

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

100 Clinical Results associated with 2-261

100 Translational Medicine associated with 2-261

100 Patents (Medical) associated with 2-261

Literatures (Medical) associated with 2-261

01 Nov 2022·Neuropharmacology

Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice

Article

Author: Johnstone, T B ; Genaro, K ; Hogenkamp, D J ; Yoshimura, R F ; Gee, K W ; Doan, B P

The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABA_ARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABA_ARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABA_ARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABA_ARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABA_A δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABA_ARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABA_ARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.

01 Sep 2021·Toxicology and Applied PharmacologyQ3 · MEDICINE

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Q3 · MEDICINE

Article

Author: Lein, Pamela J ; Carty, Dennis R ; Pressly, Brandon ; Yaghoobi, Bianca ; Wulff, Heike ; Mundy, Paige C

The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA _AR) antagonist that causes life threatening seizures. Currently, there is no specific antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABA_ARs. The major target of TETS was recently identified as the GABA_AR α2β3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABA_AR subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2-261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2-261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant.

01 Jan 2019·PainQ1 · MEDICINE

Positive allosteric modulators of nonbenzodiazepine γ-aminobutyric acidA receptor subtypes for the treatment of chronic pain

Q1 · MEDICINE

Article

Author: Johnstone, Timothy B C ; Porreca, Frank ; Xie, Jennifer Y ; Gee, Kelvin W ; Wasiak, David J ; Hogenkamp, Derk J ; Qu, Chaoling

AbstractChronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABAAR-mediated currents by agonist ligands for δ subunit–containing GABAARs. However, typical ligands that target δ subunit–containing GABAARs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2-261, a nonbenzodiazepine site positive allosteric modulator of α4β3δ GABAARs optimized to be nonsedative by selective activation of β2/3-subunit–containing GABAARs over receptor subtypes incorporating β1 subunits. Similar levels of 2-261 were detected in the brain and plasma after intraperitoneal administration. Although systemic 2-261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABAAR-dependent fashion. Intrathecal 2-261 produced conditioned place preference and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated, rats. In addition, systemic pretreatment with 2-261 blocked conditioned place preference from spinal clonidine in SNL rats. Moreover, 2-261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2-261 likely required interaction with the α4β3δ GABAAR because 2-301, a close structural analog of 2-261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2-261 may produce pain relief with diminished side effects through selective modulation of β2/3-subunit–containing extrasynaptic GABAARs.

100 Deals associated with 2-261

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Indication	Highest Phase	Country/Location	Organization	Date
Neuralgia	Discovery	US	University of California, Irvine Extension	-
Neuralgia	Discovery	US	University of Arizona	-

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