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ACS Med Chem Lett. 2017 Sep 1;8(10):1110-1115. doi: 10.1021/acsmedchemlett.7b00317. eCollection 2017.

Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines.

Author information

  • 1Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.

Abstract

Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

KEYWORDS:

Positive allosteric modulator (PAM); Rett syndrome; VU6005649; cognition; metabotropic glutamate receptor 7 (mGlu7)

PMID:
29057060
PMCID:
PMC5641958
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00317
[PubMed]
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