title: Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids.
abstract: Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are both antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents. All of these compounds possess antagonist activity at group I mGluRs but are inactive at group II and III mGluRs.
authors.affiliation: NeuroScience PharmaBiotec Research Center, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: Hasse
authors.initials: H
authors.lastname: Kromann
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sløk
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D000242:Cyclic AMP