title: In vivo seizure induction and affinity studies of domoic acid and isodomoic acids-D, -E and -F.
abstract: Domoic acid and its isomers are produced via algal blooms and are found in high concentrations in shellfish. Here, we assessed the acute seizurogenic potencies of isomers-D, -E and -F and their binding affinities at heterogeneous populations of KA receptors from rat cerebrum. In addition, binding affinities of all six isomers (Iso-A through -F) were assessed at AMPA receptors. Radioligand displacement studies indicated that the seizurogenic potency of Iso-F (E-configuration) closely correlates with its affinities at both KA and AMPA receptors, whereas isomers-D (Z) and -E (E), which exhibit distinctly lower seizurogenic potencies, are quite weak displacers. Previously observed functional potencies for isomers-A, -B and -C (Sawant et al., 2008) correlated with AMPA receptor affinities observed here. Taken together, these findings call into question previous structure-activity rules. Significantly, in our hands, Iso-D was ten-fold less potent than Iso-F. To further explain observed links between structural conformation and functional potency, molecular modeling was employed. Modeling results closely matched the rank order of potency and binding data observed. We further assessed the efficacy of isomers-D, -E and -F as pharmacological preconditioning agents. Acute preconditioning with low-dose Iso-D, -E or -F, before high-dose DA failed to impart behavioural tolerance. This study has shed new light on structural conformations affecting non-NMDA ionotropic glutamate receptor binding and functional potency, and provides a foundation for future work in areas of AMPA and KA receptor modeling.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, Dunedin, New Zealand. steve.kerr@otago.ac.nz
authors.forename: P M
authors.initials: PM
authors.lastname: Sawant
authors.forename: J D A
authors.initials: JD
authors.lastname: Tyndall
authors.forename: P T
authors.initials: PT
authors.lastname: Holland
authors.forename: B M
authors.initials: BM
authors.lastname: Peake
authors.forename: D O
authors.initials: DO
authors.lastname: Mountfort
authors.forename: D S
authors.initials: DS
authors.lastname: Kerr
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006624:Hippocampus / Q000648:ultrastructure; D007536:Isomerism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009467:Neuromuscular Depolarizing Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced*; D013574:Synaptosomes / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000493:pharmacokinetics; D000097806:GluK2 Kainate Receptor
chemical_list: D007608:Kainic Acid; D009467:Neuromuscular Depolarizing Agents; D018092:Kainic Acid Receptors; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000097806:GluK2 Kainate Receptor; C012301:domoic acid