TY - JOUR
T1 - Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands
AU - Littman, Louis
AU - Tokar, Christopher
AU - Venkatraman, Shankar
AU - Roon, Robert J.
AU - Koerner, James F.
AU - Robinson, Michael B.
AU - Johnson, Rodney L.
PY - 1999/5/6
Y1 - 1999/5/6
N2 - 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.
AB - 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.
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U2 - 10.1021/jm9806897
DO - 10.1021/jm9806897
M3 - Article
C2 - 10229632
AN - SCOPUS:0033529085
SN - 0022-2623
VL - 42
SP - 1639
EP - 1647
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 9
ER -