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

The conformationally constrained cyclobutane analogues of quisqualic acid ( Z)- and (E)-1-amino-3-[2'-(3',5'-dioxo-1',2',4'-oxadiazolidinyl)]cyclobutan e-1-carboxylic acid, compounds 2 and 3, respectively, were synthesized. Bot h 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus wi th EC50 values of 18 +/- 6 and 53 +/- 19 mu M, respectively. Neither analog ue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a recept ors. 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 mu M, while that for 3 was 49 +/- 25 mu M. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. I n addition, neither compound blocked [H-3]glutamic acid uptake into synapto somal membranes, and neither compound was able to produce the QUIS effect a s does quisqualic acid. This pharmacological profile indicates that 2 and 3 are selective ligands for the mGluR5a metabotropic glutamic acid receptor.