4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.
Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.
Pedregal
C
C
Lilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain.
Collado
I
I
Escribano
A
A
Ezquerra
J
J
Domínguez
C
C
Mateo
A I
AI
Rubio
A
A
Baker
S R
SR
Goldsworthy
J
J
Kamboj
R K
RK
Ballyk
B A
BA
Hoo
K
K
Bleakman
D
D
D000114:Acetylene / Q000737:chemistry; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000502:physiology; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000114:Acetylene; D005971:Glutamates; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C117450:2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid