Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A‐841720, a novel non‐competitive mGluR1 receptor antagonist

Abstract

Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC 50 values of 10.773.9 and 1.070.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED 50 ¼ 23 mmol kg À1 ) and monoiodoacetate-induced joint pain (ED 50 ¼ 43 mmol kg À1 ). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED 50 ¼ 28 and 27 mmol kg À1 , respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications. The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

“…mGlu2/3-receptor agonists have been reported not to improve either the NMDA-receptor antagonists-induced impairment of working memory (39) or the NMDAreceptor antagonist-induced impairment of object recognition (40), although mGlu2/3-receptor agonists improved object recognition impairment in rodents reared in social isolation or in mice lacking the pituitary adenylate cyclase-activating polypeptide (41 -43). Moreover, the stimulation of the mGlu2 receptor or the blockade of the mGlu1 receptor reportedly caused cognitive impairment itself (19,44,45). Although these discrepancies might be explained by differences in the experimental conditions and models that were used, the efficacy of mGlu2/3-receptor agonists and mGlu1-receptor antagonists for cognitive dysfunction has to be fully addressed in future studies.…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…A-841720 was also active against Freund's adjuvantinduced inflammatory pain with an ED 50 of 23 mol/kg i.p. and reduced mechanical allodynia in sciatic nerve constriction and spinal nerve ligation models of neuropathic pain in the same dose range (El-Kouhen et al, 2006). However, significant motor side effects occurred at analgesic doses, and the compound also impaired cognitive function in Y-maze and water maze tests.…”

Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

“…The recently reported novel mGluR1 antagonist YM-298198 is thought to be a selective mGluR1 antagonist with oral activity while only potency toward rat, but not human, mGluR1 has been reported previously (Kohara et al, 2005). More recently, a new mGluR1 antagonist, A-841720, has been shown to be systemically active in rodent pain models (Zheng et al, 2005;El-Kouhen et al, 2006). However, the antagonistic activity of the compound toward human mGluR1 is 10-fold less potent than that toward rat mGluR1 and its selectivity between human mGluR1 and mGluR5 is not very high (about 30-fold) comparing other known noncompetitive mGluR1 antagonists.…”