Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology

作者：Hammond Alexis S; Rodriguez Alice L; Townsend Steven D; Niswender Colleen M; Gregory Karen J; Lindsley Craig W; Conn P Jeffrey^*

来源：ACS Chemical Neuroscience, 2010, 1(10): 702-716.

DOI：10.1021/cn100051m

• mGlu(5)
• metabotropic
• glutamate
• allosteric
• potentiator

We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxol,3-dihydro-2H-isoindo1-2-yl)methyl]pheny1}-2-hydroxy- benzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure activity relationship (SAR), poor physio-chemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC50 = 1.3 mu M, 106% Glu(max)) and VU0040237 (EC50 = 350 nM, 84% Glu(Max)). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VUO357121 (EC50 = 33 nM, 92% Glum(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VUO365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VUO357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.

• 出版日期2010-10