A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5 - PubMed

Affiliations

• PMID: 12920211
• DOI: 10.1124/mol.64.3.731

A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5

Julie A O'Brien et al. Mol Pharmacol. 2003 Sep.

Abstract

We have identified a family of highly selective allosteric modulators of the group I metabotropic glutamate receptor subtype 5 (mGluR5). This family of closely related analogs exerts a spectrum of effects, ranging from positive to negative allosteric modulation, and includes compounds that do not themselves modulate mGluR5 agonist activity but rather prevent other family members from exerting their modulatory effects. 3,3'-Difluorobenzaldazine (DFB) has no agonist activity, but it acts as a selective positive allosteric modulator of human and rat mGluR5. DFB potentiates threshold responses to glutamate, quisqualate, and 3,5-dihydroxyphenylglycine in fluorometric Ca2+ assays 3- to 6-fold, with EC50 values in the 2 to 5 microM range, and at 10 to 100 microM, it shifts mGluR5 agonist concentration-response curves approximately 2-fold to the left. The analog 3,3'-dimethoxybenzaldazine (DMeOB) acts as a negative modulator of mGluR5 agonist activity, with an IC50 of 3 microM in fluorometric Ca2+ assays, whereas the analog 3,3'-dichlorobenzaldazine (DCB) does not exert any apparent modulatory effect on mGluR5 activity. However, DCB seems to act as an allosteric ligand with neutral cooperativity, preventing the positive allosteric modulation of mGluRs by DFB as well as the negative modulatory effect of DMeOB. None of these analogs affects binding of [3H]quisqualate to the orthosteric (glutamate) site, but they do inhibit [3H]3-methoxy-5-(2-pyridinylethynyl)pyridine binding to the site for 2-methyl-6-(phenylethynyl)-pyridine, a previously identified negative allosteric modulator. With the use of these compounds, we provide evidence that allosteric sites on GPCRs can respond to closely related ligands with a range of pharmacological activities from positive to negative modulation as well as to neutral competition of this modulation.

Similar articles

• A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain.

  O'Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr. O'Brien JA, et al. J Pharmacol Exp Ther. 2004 May;309(2):568-77. doi: 10.1124/jpet.103.061747. Epub 2004 Jan 27. J Pharmacol Exp Ther. 2004. PMID: 14747613

• A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.

  Kinney GG, O'Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr. Kinney GG, et al. J Pharmacol Exp Ther. 2005 Apr;313(1):199-206. doi: 10.1124/jpet.104.079244. Epub 2004 Dec 17. J Pharmacol Exp Ther. 2005. PMID: 15608073

• Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential.

  Kew JN. Kew JN. Pharmacol Ther. 2004 Dec;104(3):233-44. doi: 10.1016/j.pharmthera.2004.08.010. Pharmacol Ther. 2004. PMID: 15556676 Review.

• Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists.

  Johnson MP, Nisenbaum ES, Large TH, Emkey R, Baez M, Kingston AE. Johnson MP, et al. Biochem Soc Trans. 2004 Nov;32(Pt 5):881-7. doi: 10.1042/BST0320881. Biochem Soc Trans. 2004. PMID: 15494040 Review.

Cited by

• Studies of the metabotropic glutamate receptor 5 radioligand [¹¹C]ABP688 with N-acetylcysteine challenge in rhesus monkeys.

  Sandiego CM, Nabulsi N, Lin SF, Labaree D, Najafzadeh S, Huang Y, Cosgrove K, Carson RE. Sandiego CM, et al. Synapse. 2013 Aug;67(8):489-501. doi: 10.1002/syn.21656. Epub 2013 Mar 27. Synapse. 2013. PMID: 23424090 Free PMC article.

• Effects of positive allosteric modulators on single-cell oscillatory Ca2+ signaling initiated by the type 5 metabotropic glutamate receptor.

  Bradley SJ, Watson JM, Challiss RA. Bradley SJ, et al. Mol Pharmacol. 2009 Dec;76(6):1302-13. doi: 10.1124/mol.109.059170. Epub 2009 Sep 8. Mol Pharmacol. 2009. PMID: 19737913 Free PMC article.

• Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity.

  Marlo JE, Niswender CM, Days EL, Bridges TM, Xiang Y, Rodriguez AL, Shirey JK, Brady AE, Nalywajko T, Luo Q, Austin CA, Williams MB, Kim K, Williams R, Orton D, Brown HA, Lindsley CW, Weaver CD, Conn PJ. Marlo JE, et al. Mol Pharmacol. 2009 Mar;75(3):577-88. doi: 10.1124/mol.108.052886. Epub 2008 Dec 1. Mol Pharmacol. 2009. PMID: 19047481 Free PMC article.

• Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications.

  Yin S, Niswender CM. Yin S, et al. Cell Signal. 2014 Oct;26(10):2284-97. doi: 10.1016/j.cellsig.2014.04.022. Epub 2014 May 2. Cell Signal. 2014. PMID: 24793301 Free PMC article. Review.

• Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

  Conn PJ, Christopoulos A, Lindsley CW. Conn PJ, et al. Nat Rev Drug Discov. 2009 Jan;8(1):41-54. doi: 10.1038/nrd2760. Nat Rev Drug Discov. 2009. PMID: 19116626 Free PMC article. Review.

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • Guide to Pharmacology

• Miscellaneous

  • NCI CPTAC Assay Portal