title: A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain.
abstract: GABA(A) 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.
authors.affiliation: Discovery Biology, Pfizer Inc., Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nickolls
authors.forename: Hannah
authors.initials: H
authors.lastname: Mace
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fish
authors.forename: Michelle
authors.initials: M
authors.lastname: Edye
authors.forename: Rachel
authors.initials: R
authors.lastname: Gurrell
authors.forename: Magnus
authors.initials: M
authors.lastname: Ivarsson
authors.forename: Tom
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authors.lastname: Pitcher
authors.forename: Sachi
authors.initials: S
authors.lastname: Tanimoto-Mori
authors.forename: Denise
authors.initials: D
authors.lastname: Richardson
authors.forename: Catherine
authors.initials: C
authors.lastname: Sweatman
authors.forename: Janet
authors.initials: J
authors.lastname: Nicholson
authors.forename: Cameron
authors.initials: C
authors.lastname: Ward
authors.forename: John
authors.initials: J
authors.lastname: Jinks
authors.forename: Christine
authors.initials: C
authors.lastname: Bell
authors.forename: Kimberly
authors.initials: K
authors.lastname: Young
authors.forename: Huw
authors.initials: H
authors.lastname: Rees
authors.forename: Andrew
authors.initials: A
authors.lastname: Moss
authors.forename: Ross
authors.initials: R
authors.lastname: Kinloch
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray