Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu_2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

Abstract

As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure–activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4–8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine

“…Recent studies have shown that mGluR2/3 positive allosteric positive modulators, which have enhanced receptor subtype selectivity, decrease cocaine intake in dependent animals (Dhanya et al, 2014). Using compounds with mGluR subtype selectivity is potentially useful as mGluR 2 and 3 show differential function and location.…”

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…80,81 Briefly, cells were plated into 384-well, black-walled, clear-bottomed poly-D-lysine-coated plates at a density of 15,000 cells/20 µL/well in DMEM containing 10% dialyzed FBS, 20 mM HEPES, and 100 units/mL penicillin/streptomycin (assay media). Plated cells were incubated overnight at 37°C in the presence of 5% CO 2 .…”

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

“…One effort centered on the preparation and evaluation of a number of isoindolinone analogues such as 52 (Y = CH 2 ) and benzisothiazolone analogues such as 53 (Y = S). 266 Functional mGlu 2 activity, passive membrane permeability, rat plasma stability, and rat liver microsomal stability were assessed to evaluate the new compounds. Five optimized compounds were evaluated in rat PK studies, and all exhibited generally poor CNS penetration (brain/plasma K p ≤ 0.13); however, compound 52 was a low-clearance compound with good bioavailability and attained brain levels consistent with its mGlu 2 PAM functional potency following oral dosing.…”