Previous studies indicate that agonists of the group II
metabotropic glutamate receptors (mGluRs),
mGluR2 and
mGluR3, may provide a novel approach for the treatment of
anxiety disorders and
schizophrenia. However, the relative contributions of the
mGluR2 and
mGluR3 subtypes to the effects of the group II mGluR agonists remain unclear. In the present study, we describe an alternate synthesis and further pharmacological characterization of a recently reported positive allosteric modulator of
mGluR2 termed
biphenyl-indanone A (BINA). In recombinant systems, BINA produced a robust and selective potentiation of the response of
mGluR2 to
glutamate with no effect on the
glutamate response of other mGluR subtypes. In hippocampal brain slices, BINA (1 microM) significantly potentiated the
mGluR2/3 agonist-induced inhibition of excitatory synaptic transmission at the medial perforant path-dentate gyrus synapse. BINA was also efficacious in several models predictive of
antipsychotic- and
anxiolytic-like activity in mice. The behavioral effects of BINA were blocked by the
mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)
propanoic acid (
LY341495), suggesting that the in vivo effects of BINA are mediated by increased activation of
mGluR2. Collectively, these results indicate that BINA is a selective
mGluR2 positive allosteric modulator and provide further support for the growing evidence that selective allosteric potentiators of
mGluR2 mimic many of the in vivo actions of
mGluR2/3 agonists that may predict therapeutic utility of these compounds.