A novel mechanism for pain therapeutics

Abstract

NTP-2014 is the first in a new class of compounds which offers the potential to deliver broad spectrum pain relief via an entirely new mechanism of action. Compounds in this class increase inhibitory action at GABAA receptor synapses in a state dependent fashion, not by increasing GABA activity at postsynaptic receptors, but by shutting down the inhibitory action of pre-synaptic GABAA receptors. Acting as a non-competitive antagonist of the pre-synaptic type GABA α4 receptors, without activity at post-synaptic α1, a2 or a3 GABAA receptors, yields significant pain behavior modification without sedation. Substantial preclinical, in vivo studies have been completed. In a neuropathic/inflammatory pain model in mice, NTP-2014 rapidly and significantly decreased the pain response to formalin injection into the hindpaw in a dose-dependent manner (∼99% decrease in pain behavior in the late phase of this pain model). In models of neuropathic pain, NTP-2014 demonstrated a 100% response as measured by mechanical allodynia in a chemotherapy-induced peripheral neuropathy model in rats and an 80% response in a spinal nerve ligation model (Chung) in mice. Unlike most neuropathic pain drugs, NTP-2014 also demonstrated a profound effect in an acute nociceptive pain model, the tail flick assay (∼90% response). In this assay, the compound demonstrated marked activity at the first time-point tested- as early as 10 minutes post- IP or oral dose. In a model of inflammatory pain (carrageenan paw), NTP-2014 generated a near 100% anti-nociceptive effect. This unique and specific mechanism, which acts in a very different way than traditional GABAergic drugs, has the potential to generate strong efficacy in multiple hyper-excitable states (e.g. chronic and acute pain, epilepsy and migraine) without generating typical CNS side effects (e.g. sedation and decreased cognition). Research sponsored by NeuroTherapeutics Pharma, Chicago IL.