Phenyl-tetrazolyl Acetophenones:  Discovery of Positive Allosteric Potentiatiors for the Metabotropic Glutamate 2 Receptor

Abstract

Herein we disclose the discovery of a new class of positive allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2), phenyl-tetrazolyl acetophenones, e.g. 1-(2-hydroxy-3-propyl-4-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl) ethanone (4). These potentiators were shown to have no effect in the absence of glutamate as well as no effect at mGlu3 or the other mGlu receptors. The compounds were also evaluated in rodent models with potential relevance for schizophrenia, and 4 was shown to have activity in the inhibition of ketamine-induced norepinephrine release and ketamine-induced hyperactivity. This represents the first example of the efficacy of mGlu2 receptor potentiators in these models.

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…Another class of positive allosteric mGlu2 receptor modulators, phenyl-tetrazolyl acetophenones, was discovered at Merck research laboratories also by HTS using a FLIPR calcium assay in a cell line coexpressing the human mGlu2 receptor and the promiscuous G-protein G␣ 16 (Pinkerton et al, 2004b). In a secondary confirmation assay, the lead compound (compound VII in Table 8) increased the potency (and slightly the maximal response) of glutamate in stimulating GTP␥ 35 S binding via mGlu2 receptors, but not mGlu3 or other mGlu receptors.…”

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

“…The first in a series of applications disclosed such arylketone derivatives where acetophenones were linked with an aryl ether linker to an acidic phenyl tetrazole scaffold. Representative compound 5, identified by in-house high-throughput screening had an EC 50 value of 328 nM and found to be selective over other mGluR receptors [39]. The structureactivity relationships (SAR) of these derivatives have been reported in a separate paper [40].…”

“…The structure-activity relationships of these derivatives have been reported in a separate paper [98]. The most promising compound, 49, was identified starting from a hit compound, 3, identified by a HTS screening campaign [39,40] (Figure 11). This compound is an mGluR2-selective PAM that is moderately brain penetrant (B/P = 0.16), has acceptable rat PK, and most importantly, significantly attenuated ketamine-induced hyperactivity at 40 mg/kg i.p.…”

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…Another series of compounds results from 4'-alkoxyacetophenone derivatives, and is typified by compound 1. Compound 1 is a selective mGlu2 receptor potentiator (300 nM) with no allosteric activities against mGlu1, 3, 4, 5, 7 or 8 [106,107].…”