Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2

Abstract

Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

“…Although LY379268-mediated depression of electrically-evoked field potentials was previously shown to require mGlu 2 (Zhou et al, 2013), pharmacological analysis of the individual contributions of mGlu 2 and mGlu 3 has not been reported. To directly evaluate the role of each receptor in non-transgenic mice, we used two recently reported negative allosteric modulators (NAMs), VU6001192 and VU0469942, which are selective for mGlu 2 and mGlu 3 , respectively (Felts et al, 2015; Wenthur et al, 2013). Incubation of slices with VU6001192 (10 μM, present throughout recording) completely prevented the LY379268-mediated depression of eEPSC amplitude (control 50.0 ± 8.2% of baseline, n = 10, vs. VU6001192 99.7 ± 11.0% of baseline, n = 6, at 6–10 minutes following onset of LY379268 application), whereas VU0469942 (10 μM, present throughout recording) did not block the effect of LY379268 (56.6 ± 4.6% of baseline; n = 6).…”

Differential Pharmacology and Binding of mGlu2 Receptor Allosteric Modulators

“…All drugs were synthesized in house through previously described methods unless otherwise noted. The mGlu 2/3 NAMs [1,4] diazepin-2-yl)-pyridine-2-carbonitrile] and decoglurant (5-[2-[7-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3yl]ethynyl] pyridin-2-amine)) and mGlu 2 NAMs (MRK-8-29 (4-(2-fluoro-4-methoxyphenyl)-7-(2-(2-methylpyrimidin-5-yl)ethyl)quinoline-2-carboxamide) and VU6001192 (6-((cis-2,6-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4oxo-1,4-dihydroquinoline-3-carboxamide)) were synthesized as described previously (Hemstapat et al, 2007;Felts et al, 2015;Walker et al, 2015). Likewise, the mGlu 2 PAMs, AZD8529 (7-methyl-…”

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

“…32,33 While a wide range of highly selective mGlu 2 PAMs have been discovered and recently reviewed, 33,34 the development of selective mGlu 2 NAMs has remained in its nascent stage with only one report based on a dihydroquinoline 2-carboxamide scaffold in the primary literature. 35 …”