title: Analogues of homoibotenic acid show potent and selective activity following sensitisation by quisqualic acid.
abstract: Quisqualic acid induces sensitisation of neurones to depolarisation by analogues of 2-amino-4-phosphonobutyric acid (AP4), phenylglycine, and homoibotenic acid (HIBO). Thus, after administration of quisqualate these analogues become active at concentrations at which they are otherwise inactive. The mechanisms behind quisqualate-induced sensitisation are poorly understood and have not previously been quantified properly. In this study, we have tested the activity of a number of 4-alkyl- and 4-aryl-substituted analogues of HIBO as regards quisqualate-sensitisation, and present a method for quantifying the sensitisation induced by quisqualate at cortical neurones. These analogues are generally more potent and selective than (S)-AP4 or its homologue (S)-AP5 following quisqualate-sensitisation. Furthermore, we found a statistically significant correlation between the ligands' ability to inhibit CaCl(2)-dependent (S)-[(3)H]glutamate uptake into rat cortical synaptosomes, and their potency following quisqualate-induced depolarisation. This demonstrates the involvement of a transport system in the mechanism underlying the quisqualate-effect.
authors.affiliation: Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen Ø, Denmark. htv@dfuni.dk
authors.forename: Henrik T
authors.initials: HT
authors.lastname: Vestergaard
authors.forename: Stine B
authors.initials: SB
authors.lastname: Vogensen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D002122:Calcium Chloride / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D007051:Ibotenic Acid; D018698:Glutamic Acid; C008852:2-phenylglycine; C023364:homoibotenic acid; D016318:Quisqualic Acid; C012729:2-amino-4-phosphonobutyric acid; D002122:Calcium Chloride; D005998:Glycine