Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice.
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.
Galici
Ruggero
R
Program in Translational Neuropharmacology, Department of Pharmacology, Vanderbilt University Medical Center, 23rd Ave. S. at Pierce, 417-D Preston Research Building, Nashville, TN 37232-6600, USA.
Jones
Carrie K
CK
Hemstapat
Kamondanai
K
Nong
Yi
Y
Echemendia
Nicholas G
NG
Williams
Lilly C
LC
de Paulis
Tomas
T
Conn
P Jeffrey
PJ
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D001713:Biphenyl Compounds; D007189:Indans; D018094:Receptors, Metabotropic Glutamate; C522461:biphenyl-indanone A; C108822:metabotropic glutamate receptor 2; C013352:indacrinone