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Potent and specific action of the mGlu1 antagonists YM-298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices

Fukunaga, I; Yeo, CH; Batchelor, AM; (2007) Potent and specific action of the mGlu1 antagonists YM-298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices. BRIT J PHARMACOL , 151 (6) 870 - 876. 10.1038/sj.bjp.0707286. Gold open access

Abstract

Background and purpose: Specific and selective inhibitors for mGlu1 receptors are presently inadequate. A new generation of non-competitive mGlu1 antagonists with low nanomolar potencies is emerging. We evaluated two new compounds, YM-298198 and JNJ16259685, for effectiveness, potency and specificity for the first time in a brain slice preparation.Experimental approach: Patch-clamp recording of Purkinje neurones in cerebellar slices were obtained. The slow mGlu1-mediated EPSP was used to establish a concentration-response curve. Fast excitatory synaptic inputs were tested for nonspecific effects.Key results: YM-298198 and JNJ16259685 inhibited the synaptic activation of mGlu1 in a concentration-dependent manner (IC50 values of 24 nM and 19 nM, respectively). The antagonists were slow to inhibit and to reverse on washout, probably due to their lipophilic nature. There were no non-specific effects on fast AMPA receptor-mediated synaptic transmission in the cerebellum.Conclusions and implications: These compounds are more than a thousand-fold more potent than previously available compounds. Their selectivity and specificity will be very useful for studying the role of mGlu1 receptors both in vitro and in vivo.

Type: Article
Title: Potent and specific action of the mGlu1 antagonists YM-298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices
Open access status: An open access publication
DOI: 10.1038/sj.bjp.0707286
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC20141...
Keywords: metabotropic glutamate receptors, cerebellum, Purkinje cell, METABOTROPIC GLUTAMATE-RECEPTOR, LONG-TERM DEPRESSION, PURKINJE-CELLS, PHARMACOLOGICAL CHARACTERIZATION, NONCOMPETITIVE ANTAGONIST, PARALLEL FIBER, EXPRESSION, SYNAPSES, CPCCOET, BRAIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/130851
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