Broad spectrum efficacy with LY2969822, an oral prodrug of metabotropic glutamate 2/3 receptor agonist LY2934747, in rodent pain models.

Autor: Johnson MP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Muhlhauser MA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Nisenbaum ES; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Simmons RM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Forster BM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Knopp KL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Yang L; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Morrow D; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Li DL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Kennedy JD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Swanson S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Monn JA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2017 May; Vol. 174 (9), pp. 822-835. Date of Electronic Publication: 2017 Mar 13.
DOI: 10.1111/bph.13740
Abstrakt: Background and Purpose: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu 2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu 2/3 receptor agonist prodrug were investigated.
Experimental Approach: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu 2/3 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 -1 . 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 2/3 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 2/3 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 2/3 receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.
(© 2017 The British Pharmacological Society.)
Databáze: MEDLINE
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