Design and synthesis of substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides as positive allosteric modulators of the metabotropic glutamate receptor subtype 5

  • Bioorg Med Chem Lett. 2011 May 1;21(9):2650-4. doi: 10.1016/j.bmcl.2010.12.110.
Mu-Fa Zou  1 ,  Jianjing Cao ,  Alice L Rodriguez ,  P Jeffrey Conn ,  Amy Hauck Newman
Affiliations
  • 1. Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive Baltimore, MD 21224, USA.
PMID: 21295978 DOI: 10.1016/j.bmcl.2010.12.110
Abstract

Based on SAR in the alkyne class of mGlu5 receptor negative allosteric modulators and a set of amide-based positive allosteric modulators, optimized substitution of the aryl 'b' ring was used to create substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides. Results from an mGlu5 receptor functional assay, using calcium fluorescence, revealed varying efficacies and potencies that provide evidence that subtle changes in compounds within a close structural class can have marked effects on functional activity including switches in modes of efficacy (i.e., negative to positive allosteric modulation).