Display options
Cite
Zhou Y, Manka JT, Rodriguez AL, et al. Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity. ACS Med Chem Lett. 2010;1(8):433-438doi: 10.1021/ml100181a.
Zhou, Y., Manka, J. T., Rodriguez, A. L., Weaver, C. D., Days, E. L., Vinson, P. N., Jadhav, S., Hermann, E. J., Jones, C. K., Conn, P. J., Lindsley, C. W., & Stauffer, S. R. (2010). Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity. ACS medicinal chemistry letters, 1(8), 433-438. https://doi.org/10.1021/ml100181a
Zhou, Ya, et al. "Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity." ACS medicinal chemistry letters vol. 1,8 (2010): 433-438. doi: https://doi.org/10.1021/ml100181a
Zhou Y, Manka JT, Rodriguez AL, Weaver CD, Days EL, Vinson PN, Jadhav S, Hermann EJ, Jones CK, Conn PJ, Lindsley CW, Stauffer SR. Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity. ACS Med Chem Lett. 2010 Nov 11;1(8):433-438. doi: 10.1021/ml100181a. Epub 2010 Aug 13. PMID: 23308336; PMCID: PMC3539763.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2010 Nov 11;1(8):433-438. doi: 10.1021/ml100181a. Epub 2010 Aug 13.

Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity.

ACS medicinal chemistry letters

Ya Zhou, Jason T Manka, Alice L Rodriguez, C David Weaver, Emily L Days, Paige N Vinson, Satyawan Jadhav, Elizabeth J Hermann, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Shaun R Stauffer

Affiliations

  1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA ; Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.

PMID: 23308336 PMCID: PMC3539763 DOI: 10.1021/ml100181a

Abstract

This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu(5) positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu(5) chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a 'molecular switch'. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu(5) receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR(5) PAM optimized from an HTS-derived mGluR5 competitive antagonist.

References

  1. J Pharmacol Exp Ther. 2005 Apr;313(1):199-206 - PubMed
  2. Mol Pharmacol. 2008 Mar;73(3):909-18 - PubMed
  3. J Pharmacol Exp Ther. 2008 Dec;327(3):827-39 - PubMed
  4. J Pharmacol Exp Ther. 2004 May;309(2):568-77 - PubMed
  5. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3275-8 - PubMed
  6. J Med Chem. 2009 Jul 23;52(14):4103-6 - PubMed
  7. Neuropsychopharmacology. 2009 Aug;34(9):2057-71 - PubMed
  8. Biol Psychiatry. 1999 Nov 15;46(10):1321-7 - PubMed
  9. Neuropharmacology. 2009 Oct-Nov;57(5-6):531-8 - PubMed
  10. N Engl J Med. 2005 Sep 22;353(12):1209-23 - PubMed
  11. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3209-13 - PubMed
  12. ChemMedChem. 2009 Apr;4(4):505-11 - PubMed
  13. Mol Pharmacol. 2003 Sep;64(3):731-40 - PubMed
  14. J Pharmacol Exp Ther. 2005 Dec;315(3):1212-9 - PubMed
  15. J Med Chem. 2004 Nov 18;47(24):5825-8 - PubMed
  16. Biol Psychiatry. 2009 Apr 15;65(8):717-20 - PubMed
  17. Trends Pharmacol Sci. 2009 Jan;30(1):25-31 - PubMed
  18. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1386-91 - PubMed

Publication Types

Grant support