Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands

Louis Littman, Christopher Tokar, Shankar Venkatraman, Robert J. Roon, James F. Koerner, Michael B. Robinson, Rodney L. Johnson

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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 μM, 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 μM, while that for 3 was 49 ± 25 μM. 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.

Original languageEnglish (US)
Pages (from-to)1639-1647
Number of pages9
JournalJournal of Medicinal Chemistry
Volume42
Issue number9
DOIs
StatePublished - May 6 1999

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Littman, L., Tokar, C., Venkatraman, S., Roon, R. J., Koerner, J. F., Robinson, M. B., & Johnson, R. L. (1999). Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands. Journal of Medicinal Chemistry, 42(9), 1639-1647. https://doi.org/10.1021/jm9806897