The novel antagonist 3‐CBW discriminates between kainate receptors expressed on neonatal rat motoneurones and those on dorsal root C‐fibres

• Published in: British journal of pharmacology 2002-12, Vol.137 (7), p.1125-1133
• Main Authors: More, Julia C A, Troop, Helen M, Jane, David E
• Format: Article
• Language: English
• Subjects: (S)‐3‐(4‐carboxybenzyl)willardiine; 3‐CBW; Alanine - analogs & derivatives; Alanine - chemistry; Alanine - pharmacology; AMPA; Animals; Animals, Newborn; antagonist; Benzodiazepines - pharmacology; Benzyl Compounds - pharmacology; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Dose-Response Relationship, Drug; Evoked Potentials - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; GYKI53655; kainate; Motor Neurons - drug effects; Motor Neurons - physiology; Neonatal rat spinal cord; Nerve Fibers - drug effects; Nerve Fibers - physiology; Pyrimidinones; Quinoxalines - pharmacology; Rats; Receptors, AMPA - antagonists & inhibitors; Receptors, Kainic Acid - antagonists & inhibitors; Spinal Nerve Roots - drug effects; Spinal Nerve Roots - physiology; Time Factors; Uracil; Vertebrates: nervous system and sense organs
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704957

The natural product willardiine is a selective AMPA receptor agonist. We report that an N3‐substituted analogue of willardiine, (S)‐3‐(4‐carboxybenzyl)willardiine (3‐CBW), antagonizes AMPA and kainate receptors expressed on motoneurones and dorsal root C‐fibres, respectively. Reduction of the fast component of the dorsal root‐evoked ventral root potential (fDR‐VRP) has been used as a novel method to compare AMPA receptor antagonists. 3‐CBW, NBQX and GYKI53655 depressed the fDR‐VRP with IC50 values of 10.3±2.4, 0.214±0.043 and 4.03±0.31 μM, respectively. That 3‐CBW depressed the fDR‐VRP by acting at AMPA and not metabotropic glutamate receptors was demonstrated by the lack of effect of LY341495 (100 μM). The Schild plot for antagonism of responses to (S)‐5‐fluorowillardiine on motoneurones by 3‐CBW had a slope of 1.11±0.13 giving a pA2 value of 4.48. The Schild plot for antagonism of kainate responses on the dorsal root by 3‐CBW had a slope of 1.05±0.05 giving a pA2 value of 4.96. On neonatal rat motoneurones 3‐CBW (200 μM) almost completely abolished responses to AMPA while responses to NMDA, kainate and DHPG were 101.6±11.6%, 39.4±5.8% and 110.5±9.0% of control, respectively. 3‐CBW can therefore be used to isolate kainate receptor responses from those mediated by AMPA receptors. 3‐CBW antagonized kainate‐induced responses on dorsal root C‐fibres with a pA2 value of 4.96 whereas kainate receptor mediated responses (isolated by including GYKI53655 in the medium) on motoneurones were not completely blocked by 200 μM 3‐CBW, substantiating evidence that kainate receptors on neonatal rat motoneurones differ from those on dorsal root C‐fibres. British Journal of Pharmacology (2002) 137, 1125–1133. doi:10.1038/sj.bjp.0704957