GABA-BR PAM
The amino acid GABA (g-aminobutyric acid) is the main inhibitory neurotransmitter in the adult mammalian brain and regulates many physiological and psychological processes. GABA acts through two major classes of receptors: ionotropic GABA-A (including GABA-C) receptors and metabotropic GABA-B receptors1. GABA-BR are present in most regions of the mammalian brain on presynaptic terminals and postsynaptic neurons, and are involved in the fine-tuning of inhibitory synaptic transmission. Due to their strategic position in neuronal networks to modulate the activity of the various neurotransmitter systems, GABA-BR are a target of choice for pharmacological agents intended to treat a variety of central and peripheral nervous systems disorders2.
In humans, baclofen (Kemstro/Lioresal), a marketed generic GABA-BR agonist, is widely used for its muscle relaxant properties in the control of spasticity caused by multiple sclerosis, cerebral palsy or certain injuries to the spine. Baclofen also has been shown to be a powerful analgesic agent, especially when delivered intrathecally (i.e. by injection into the spinal chord). However, CNS-mediated side effects (sedation, hypothermia, memory impairment, etc.), poor pharmacokinetic profile and rapid induction of tolerance prevent baclofen from being prescribed for pain relief, despite its analgesic properties3.
We believe that allosteric modulation provides the opportunity to potentiate GABA-BR mediated pain reduction without the side effects associated with baclofen. GABA-BR positive allosteric modulators (PAM) have already been shown to be effective in animal models of anxiety with reduced CNS-related side-effects compared to agonists4.
Addex reported in a February 2010 press release that our GABA-BR PAM is orally efficacious in rodent models of inflammatory pain (formalin test and Complete Freund's Adjuvant-induced hypersensitivity) and visceral pain (acetic acid-induced writhing). In these tests GABA-BR PAM also displays an improved tolerability profile with reduced side effects compared to baclofen.
More recently we reported in a July 2010 press release that GABA-BR PAM was effective in a preclinical model of osteoarthritis pain. Specifically, the effects of GABA-BR PAM on mechanical hyperalgesia (increased pain sensitivity) and mechanical allodynia (pain produced by a normally innocuous stimulus) were assessed in the monosodium iodoacetate (MIA) model of osteoarthritis, a model of chronic nociceptive pain. GABA-BR PAM significantly reduced mechanical hyperalgesia and showed a trend toward reducing mechanical allodynia after both acute and sub-chronic (8 days) dosing. Statistically significant antihyperalgesic activity was observed on the first day and was maintained on day 8, despite increased pain severity.
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1) Hill and Bowery, Nature 1981, 290, 149-152; Bormann, J., Trends Pharmacol. Sci. 2000, 21, 16-19
2) Bettler et al., Physiol Rev. 2004, 84, 835-867; Cryan and Kaupmann, Trends Pharmacol Sci. 2005, 26, 36-43
3) Hefferan et al, Neuroscience Letters 2006, 403, 195-200
4) Addex Patent: WO2008/056257; Cryan and al, J. Pharm: Exp. Therap. 2004, 310, 952-963