Broad Spectrum Efficacy with LY2969822, an Oral Prodrug of Metabotropic Glutamate 2/3 Receptor Agonist LY2934747, in Rodent Pain Models

Background And Purpose: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu receptor agonist prodrug were investigated.

Experimental Approach: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu receptor agonist LY2934747. Behavioural assessments of allodynia, hyperalgesia and nocifensive behaviours were determined in preclinical pain models after administration of LY2969822 0.3-10 mg·kg . In addition, the ability of i.v. LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed.

Key Results: Following treatment with LY2934747, the spontaneous activity and electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia were suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviours induced by an intraplantar injection of formalin. The on-target nature of this effect was confirmed by blockade with an mGlu receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant - induced mechanical hyperalgesia. The mGlu receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially prevented the nocifensive behaviours in the mouse acetic acid writhing model.

Conclusions And Implications: Following oral administration of the prodrug LY2969822, the mGlu receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.