Broad spectrum efficacy with LY2969822, an oral prodrug of metabotropic glutamate 2/3 receptor agonist LY2934747, in rodent pain models.
A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3receptor agonist prodrug were investigated.



After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu2/3receptor 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.



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 mGlu2/3receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant - induced mechanical hyperalgesia. The mGlu2/3receptor 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.



Following oral administration of the prodrug LY2969822, the mGlu2/3receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Michael P
MP
Johnson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Mark A
MA
Muhlhauser
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Eric S
ES
Nisenbaum
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Rosa M A
RM
Simmons
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Beth M
BM
Forster
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Kelly L
KL
Knopp
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Lijuan
L
Yang
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Denise
D
Morrow
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Dominic L
DL
Li
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Jeffrey D
JD
Kennedy
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Steven
S
Swanson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
James A
JA
Monn
D000284:Administration, Oral; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
C000597469:2-aminospiro(bicyclo(3.1.0)hexane-4,1'-cyclopropane)-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; D013141:Spiro Compounds; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3