Research Article: A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain

Date Published: November 28, 2011

Publisher: Hindawi Publishing Corporation

Author(s): Sarah Nickolls, Hannah Mace, Rebecca Fish, Michelle Edye, Rachel Gurrell, Magnus Ivarsson, Tom Pitcher, Sachi Tanimoto-Mori, Denise Richardson, Catherine Sweatman, Janet Nicholson, Cameron Ward, John Jinks, Christine Bell, Kimberly Young, Huw Rees, Andrew Moss, Ross Kinloch, Gordon McMurray.


GABAA receptors containing α2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specific α subunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy at α2/3 or efficacy at α5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

Partial Text

GABA and glycine are the main inhibitory neurotransmitters in the CNS. GABA mediates its effects through both GABAA receptors which are ligand-gated ion-channels and GABAB receptors which are GPCRs. GABAA receptors are heteropentameric, and the majority of those present in the CNS contain two α, two β, and a single γ subunit [1]. Benzodiazepines are allosteric ligands, that is, they exhibit no intrinsic activity of their own, but potentiate or inhibit the effects of GABA at receptors that contain either an α1, 2, 3, or 5 subunit [2]. GABA activation of GABAA receptors leads to the opening of their integrated chloride channels. Chloride influx inhibits transmitter release from primary afferent terminals and hyperpolarizes spinal cord neurones, decreasing the probability of firing.

The aim of this study was to determine whether GABAA   
α2/3 selective, positive allosteric modulators with varying efficacies in vitro would affect changes in in vivo, in preclinical pain models. In order to fully interpret and compare the data generated with the two compounds used, we first determined the brain GABAA receptor occupancy of both L-838,417 and TPA023 and correlated this to nonprotein bound plasma drug levels (Figure 1). In terms of Occ50 values, TPA023 was approximately 0.3 mg/kg and L-838,417 was approximately 1 mg/kg, these data are very similar to those published by Merck [21, 22]. However, as equivalent doses did not always result in equivalent plasma exposures, in subsequent studies plasma samples were always taken for PK analysis and drug levels correlated to brain GABAA   receptor RO values determined from the results described above.

In this paper, we have investigated the level of α2/3/5 efficacy required for GABAA PAMS to exhibit efficacy in preclinical pain models. We have shown that L-838,417, which exhibits moderate α2/3/5 efficacy, exhibits a significant effect in the majority (4/5) of preclinical pain models in which it was tested. Conversely, a lower-efficacy α2/3 compound, TPA023, with minimal α5 activity, only exhibited a significant analgesic effect in two out of the four preclinical pain models investigated.

We conclude that GABAA functionally selective PAMSs are likely to have broad utility in treating clinical pain. We consider, however, it is unlikely that a low-efficacy compound such as TPA023 will show sufficient efficacy in the clinic. The balance of an increasing side effect profile and efficacy will therefore have to be carefully considered when taking compounds into clinical testing. We also recommend the use of qEEG as an early marker of pharmacology in the clinical setting.




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