Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5)

This Review describes recent trends in the development of small molecule mGlu(5) positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu(5)) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu(5) PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu(5) PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed.