Unknown

Dataset Information

0

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.

SUBMITTER: Kulkarni SS 

PROVIDER: S-EPMC2894482 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

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.

Kulkarni Santosh S SS   Zou Mu-Fa MF   Cao Jianjing J   Deschamps Jeffrey R JR   Rodriguez Alice L AL   Conn P Jeffrey PJ   Newman Amy Hauck AH  

Journal of medicinal chemistry 20090601 11


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  ...[more]

Similar Datasets

| S-EPMC1924965 | biostudies-literature
| S-EPMC2871681 | biostudies-literature
| S-EPMC3535304 | biostudies-literature
| S-EPMC4755333 | biostudies-literature
| S-EPMC6947311 | biostudies-literature
| S-EPMC3588768 | biostudies-literature
| S-EPMC2664531 | biostudies-literature
| S-EPMC8252501 | biostudies-literature
| S-EPMC6271110 | biostudies-literature
| S-EPMC5952891 | biostudies-literature