title: Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands.
abstract: The conformationally constrained cyclobutane analogues of quisqualic acid (Z)- and (E)-1-amino-3-[2'-(3',5'-dioxo-1',2', 4'-oxadiazolidinyl)]cyclobutane-1-carboxylic acid, compounds 2 and 3, respectively, were synthesized. Both 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus with EC50 values of 18 +/- 6 and 53 +/- 19 microM, respectively. Neither analogue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a receptors. Compounds 2 and 3 stimulated PI hydrolysis in cells expressing mGluR5a but not in those cells expressing mGluR1a. The EC50 value for 2 was 11 +/- 4 microM, while that for 3 was 49 +/- 25 microM. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. In addition, neither compound blocked [3H]glutamic acid uptake into synaptosomal membranes, and neither compound was able to produce the QUIS effect as does quisqualic acid. This pharmacological profile indicates that 2 and 3 are selective ligands for the mGluR5a metabotropic glutamic acid receptor.
authors.affiliation: Departments of Medicinal Chemistry and Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: L
authors.initials: L
authors.lastname: Littman
authors.forename: C
authors.initials: C
authors.lastname: Tokar
authors.forename: S
authors.initials: S
authors.lastname: Venkatraman
authors.forename: R J
authors.initials: RJ
authors.lastname: Roon
authors.forename: J F
authors.initials: JF
authors.lastname: Koerner
authors.forename: M B
authors.initials: MB
authors.lastname: Robinson
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000096:biosynthesis; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D008024:Ligands; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D016318:Quisqualic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C119078:1-amino-3-(2'-(3',5'-dioxo-1',2',4'-oxadiazolidinyl))cyclobutane-1-carboxylic acid; D008024:Ligands; D010716:Phosphatidylinositols; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016318:Quisqualic Acid; D000242:Cyclic AMP