Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia.
BACKGROUND
Normalization of excessive glutamate neurotransmission through activation of the metabotropic glutamate receptor 2 (mGluR2) represents a novel and promising approach for the treatment of schizophrenia. This strategy has gained support through the evaluation of dual mGluR2/3 agonists that act directly at the glutamate (orthosteric) binding site. Importantly, clinical validation of the mechanism was achieved in a Phase II study in schizophrenia patients with mGluR2/3 agonist LY404039. Selective positive allosteric modulators (potentiators) of mGluR2 that bind to the transmembrane region of the receptor have shown efficacy in rodent models predictive of antipsychotic activity, but have yet to be evaluated in the clinic. Allosteric mGluR2 potentiators may offer advantages over orthosteric mGluR2/3 agonists as a result of their unique mode of action and ability to achieve superior mGluR2 selectivity.


OBJECTIVE
This review focuses on the structures and biological activities of small molecule potentiators of mGluR2 that appeared in the patent literature between 2006 and early 2009.


CONCLUSIONS
Potent mGluR2 potentiators that span a broad range of structural diversity have been disclosed. Narrow patent filings within select series and drug-like properties of corresponding preferred compounds suggest that development candidates have likely been nominated.
Fraley
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, West Point, PA 19486, USA. mark_fraley@merck.com
D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D010330:Patents as Topic; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
D014150:Antipsychotic Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3