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

Abstract

Chronic 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 non-benzodiazepine (BZ) site positive allosteric modulator (PAM) of α4β3δ GABAARs optimized to be non-sedative 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 following intraperitoneal administration. While 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 (CPP) and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated rats. Additionally, systemic pretreatment with 2–261 blocked CPP 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 since 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.

Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

“…Although CBD activation of TRP channels is well described in the literature [9], the upregulation and sensitization of TRP channels in an animal model of osteoarthritis may explain why CBD-induced heat hyperalgesia was not observed before and also why CBD failed to meet the desired endpoint in clinical settings [17]. Of note, CBD possesses even more favorable antinociceptive molecular targets; the antinociceptive effects of 5-HTR3A antagonists have already been described [10,18,19], similar to positive allosteric modulation of the GABAA receptor [11,20]. However, these effects may be masked through the activation of various TRP channels by CBD, as shown in the present study.…”

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats

“…A recent report has attempted to address the sedative liabilities of GABA ligands by an alternative route. A novel compound with reduced sedative liability, acting upon β2/3-subunit-containing extrasynaptic GABA A receptors, reversed both thermal-and tactile-induced hypersensitivity in spinal nerve ligated rats (Johnstone et al, 2018).…”

Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning

“…We recently reported 2-261 as a prototype non-steroid small molecule with neurosteroid-like activity at extrasynaptic α 4 β 3 δ GABA A Rs similar to allopregnanolone (Johnstone et al, 2019) or ganaxolone (unpublished observations). 2-261 and related enaminone modulators are non-steroidal small molecules that modulate synaptic GABA A Rs similar to neurosteroids (Hogenkamp et al, 2007; Gee et al, 2010; Yoshimura et al, 2014).…”