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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

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

O El-Kouhen, S G Lehto, J B Pan, R Chang, S J Baker, C Zhong, P R Hollingsworth, J P Mikusa, E A Cronin, K L Chu, S P McGaraughty, M E Uchic, L N Miller, N M Rodell, M Patel, P Bhatia, M Mezler, T Kolasa, etc.

Br J Pharmacol. 2006 Nov;149(6):761-74.

PMID: 17016515

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 IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 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 (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). 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 (ED50 = 28 and 27 micromol kg(-1), 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP869802584	A-841720		869802-58-4	Price

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