title: Synthesis and pharmacology of glutamate receptor ligands: new isothiazole analogues of ibotenic acid.
abstract: The naturally occurring heterocyclic amino acid ibotenic acid (Ibo) and the synthetic analogue thioibotenic acid (Thio-Ibo) possess interesting but dissimilar pharmacological activity at ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). Therefore, a series of Thio-Ibo analogues was synthesized. The synthesis included introduction of substituents by Suzuki and Grignard reactions on 4-halogenated 3-benzyloxyisothiazolols, reduction of the obtained alcohols, followed by introduction of the amino acid moiety by use of 2-(N-tert-butoxycarbonylimino)malonic acid diethyl ester. The obtained Thio-Ibo analogues (1, 2a-g) were characterized in functional assays on recombinant mGluRs and in receptor binding assays on native iGluRs. At mGluRs, the activity at Group II was retained for compounds with small substituents (2a-2d), whereas the Group I and Group III receptor activities for all new compounds were lost. Detection of NMDA receptor affinity prompted further characterization, and two-electrode voltage-clamp recordings at recombinant NMDA receptor subtypes NR1/NR2A-D expressed in Xenopus oocytes were carried out for compounds with small substituents (chloro, bromo, methyl or ethyl, compounds 2a-d). This series of Thio-Ibo analogues defines a structural threshold for NMDA receptor activation and reveals that the individual subtypes have different steric requirements for receptor activation. The compounds 2a and 2c are the first examples of agonists discriminating individual NMDA subtypes.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
authors.forename: Charlotte G
authors.initials: CG
authors.lastname: Jørgensen
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Bjørn
authors.initials: B
authors.lastname: Metzler
authors.forename: Birgitte Bjørn
authors.initials: BB
authors.lastname: Metzler
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D008024:Ligands; D008314:Malonates / Q000737:chemistry; D008956:Models, Chemical; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014981:Xenopus / Q000378:metabolism
chemical_list: D000438:Alcohols; D000596:Amino Acids; D008024:Ligands; D008314:Malonates; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; C494664:thioibotenic acid; D007051:Ibotenic Acid