title: LY339434, a GluR5 kainate receptor agonist.
abstract: The activity of a gamma-substituted glutamate analogue, (2S, 4R, 6E)-2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid (LY339434) and (2S,4R)-4-methylglutamic acid at ionotropic glutamate receptors has been examined. Ligand binding studies were performed using [3H] AMPA binding to membranes expressing either homomeric recombinant GluR1, GluR2, GluR4 receptors, and [3H] kainate binding to GluR5 and GluR6 kainate receptors. LY339434 and (2S,4R)-4-methylglutamic acid showed selectivity in ligand binding studies for kainate receptors over AMPA receptors. Within the kainate class of glutamate receptors, LY339434 showed selectivity for GluR5 over GluR6 whereas (2S,4R)-4-methylglutamic acid showed high affinity for both GluR5 and GluR6 kainate receptors. Examination of the functional activity of LY339434 and (2S,4R)-4-methylglutamic acid showed that both compounds evoked inward currents in dorsal root ganglion neurons (DRG) with estimated EC50 values of 0.8 +/- 0.2 microM and 0.17 +/- 0.04 microM, respectively. In GluR5 expressing HEK 293 cells, LY339434 evoked inward currents with an estimated EC50 value of 2.5 +/- 0.9 microM but had little effect on GluR6 expressing cells at concentrations less than 100 microM. LY339434 was a weak AMPA receptor agonist (EC50 values > 300 microM) as determined by activity in acutely isolated cerebellar Purkinje neurons. LY339434 and (2S,4R)-4-methylglutamic acid had agonist activity at NMDA receptors studied in cultured hippocampal neurons with EC50s of 2.5 microM and 11.7 microM, respectively. These results indicate that both LY339434 and (2S,4R)-4-methyl glutamic acid may be useful pharmacological tools for the examination of kainate receptors.
authors.affiliation: Lilly Research Centre, Windlesham, Surrey, UK.
authors.forename: B
authors.initials: B
authors.lastname: Small
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Kemp
authors.forename: K
authors.initials: K
authors.lastname: Hoo
authors.forename: B
authors.initials: B
authors.lastname: Ballyk
authors.forename: M
authors.initials: M
authors.lastname: Deverill
authors.forename: A M
authors.initials: AM
authors.lastname: Ogden
authors.forename: A
authors.initials: A
authors.lastname: Rubio
authors.forename: C
authors.initials: C
authors.lastname: Pedregal
authors.forename: D
authors.initials: D
authors.lastname: Bleakman
mesh_terms: D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D005977:Glutarates / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D005971:Glutamates; D005977:Glutarates; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C117450:2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid; C046105:4-methylglutamic acid