Structure−Activity Relationships Comparing N-(6-Methylpyridin-yl)-Substituted Aryl Amides to 2-Methyl-6-(substituted-arylethynyl)pyridines or 2-Methyl-4-(substituted-arylethynyl)thiazoles as Novel Metabotropic Glutamate Receptor Subtype 5 Antagonists

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range) 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

“…Introduction of a halide in the 3-position was well tolerated but led to a slight loss in potency [5-(3-chlorophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole (VU0067144), IC 50 ϭ 240 nM; and 5-(3-bromophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole (VU0255037), IC 50 ϭ 215 nM]. As described previously (Kulkarni et al, 2009), both potency and affinity were enhanced with the introduction of a 3-cyano-5-fluoro substitution pattern (VU0285683). VU0285683 acts as a full antagonist, completely blocking the glutamate response to mGluR5 in a concentration-dependent manner (IC 50 ϭ 24.4 Ϯ 3.6 nM, mean Ϯ S.E.M., n ϭ 3 experiments) and was found to fully compete with the equilibrium binding of [ 3 H]methoxyPEPy (K i ϭ 16.9 Ϯ 1.1 nM, mean Ϯ S.E.M., n ϭ 3 experiments; see Supplemental Fig.…”

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

“…Alternatively, the amide bond can also be envisioned as an acetylene isostere which has been successfully demonstrated previously using a diarylamide backbone. 100 In fact, several of these NAM acetylene isosteres were shown to retain affinity for the MPEP site, particularly for analogues containing a 3-CN group, and X-ray and modeling studies strongly support overlapping pharmacophore features. 100 However, at concentrations up to 100 μM, 3 orders of magnitude above that required for PAM activity, the amide based PAMs described, including 84 and 85 and the more optimized compounds 86 and 87, did not inhibit binding of [3H]methoxyPEPy, suggesting that these amides are enhancing glutamate activity via an allosteric site outside the MPEP-site.…”

“…100 In fact, several of these NAM acetylene isosteres were shown to retain affinity for the MPEP site, particularly for analogues containing a 3-CN group, and X-ray and modeling studies strongly support overlapping pharmacophore features. 100 However, at concentrations up to 100 μM, 3 orders of magnitude above that required for PAM activity, the amide based PAMs described, including 84 and 85 and the more optimized compounds 86 and 87, did not inhibit binding of [3H]methoxyPEPy, suggesting that these amides are enhancing glutamate activity via an allosteric site outside the MPEP-site. In addition, PAM 87 (VU0357121) was unable to surmount the effect of the SAM 5MPEP (88, Figure 13) on potentiation, showing a progressive rightward shift in the concentration response curve and diminution of the maximal response with increasing 5MPEP concentrations, suggesting a noncompetitive interaction between these two allosteric ligands and mGlu 5 .…”

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

“…The much more potent antagonist MPEP was then obtained as a result of a structural derivatization program starting from SIB-1757 and SIB-1893 . In a recombinant cell line expressing the human mGlu5a receptor, MPEP completely inhibited quisqualate-induced phosphoinositol hydrolysis with an IC 50 of 36 nM, corresponding to a 100-fold increase in potency compared with Jaeschke et al (2008) and by Lindsley and Emmitte (2009 Kulkarni et al, 2009 72 URWYLER the two SIB compounds. MPEP was somewhat later found to inhibit constitutive activity in a cell line transiently overexpressing the rat mGlu5 receptor, suggesting inverse agonist activity of the compound (Pagano et al, 2000).…”