Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders

doi:10.1021/acsmedchemlett.8b00450

. 2019 Jan 23;10(3):228-236.

doi: 10.1021/acsmedchemlett.8b00450. eCollection 2019 Mar 14.

Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders

Simone Brogi^{1

2}, Giuseppe Campiani¹, Margherita Brindisi¹, Stefania Butini¹

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100 Siena, Italy.
² Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131 Napoli, Italy.

PMID: 30891118
PMCID: PMC6421537
DOI: 10.1021/acsmedchemlett.8b00450

Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders

Simone Brogi et al. ACS Med Chem Lett. 2019.

. 2019 Jan 23;10(3):228-236.

doi: 10.1021/acsmedchemlett.8b00450. eCollection 2019 Mar 14.

Authors

Simone Brogi^{1

2}, Giuseppe Campiani¹, Margherita Brindisi¹, Stefania Butini¹

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100 Siena, Italy.
² Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131 Napoli, Italy.

PMID: 30891118
PMCID: PMC6421537
DOI: 10.1021/acsmedchemlett.8b00450

Abstract

The allosteric targeting of ionotropic glutamate receptors (iGluRs) is a valuable approach for treating various central nervous system (CNS) disorders. In this frame, this Innovations provides a summary of the state-of-the art in the development of allosteric modulators for iGluRs and offers an outlook regarding innovative strategies for treating neurological diseases.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Figure 1**
Chemical structures of DETQ (PAM selective for dopamine receptor-1), SB269652 (NAM selective for dopamine receptors-2/3), and representative approved allosteric modulators.

**Figure 2**
Structural view of AMPA (A) and NMDA (B) receptors highlighting known allosteric binding sites for PAMs and NAMs. (Pictures were generated by PyMOL using the PDBs 5WEO (AMPAR) and 4PE5 (NMDAR) and the information in ref (9).)

**Figure 3**
Chemical structures of γ-8 TARP-dependent-AMPARs antagonists (LY3130481/CERC-611, JNJ-55511118, and JNJ-56022486) and γ-2 TARP AMPARs modulators (VU0612951, VU0627849, and VU0539491).

See this image and copyright information in PMC

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References

1. Changeux J. P.; Christopoulos A. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell 2016, 166, 1084–1102. 10.1016/j.cell.2016.08.015. - DOI - PubMed
1. Johnstone S.; Albert J. S. Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective. Bioorg. Med. Chem. Lett. 2017, 27, 2239–2258. 10.1016/j.bmcl.2017.03.084. - DOI - PubMed
1. Nussinov R.; Tsai C. J.; Csermely P. Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol. Sci. 2011, 32, 686–693. 10.1016/j.tips.2011.08.004. - DOI - PMC - PubMed
1. Foster D. J.; Conn P. J. Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders. Neuron 2017, 94, 431–446. 10.1016/j.neuron.2017.03.016. - DOI - PMC - PubMed
1. Bruns R. F.; Mitchell S. N.; Wafford K. A.; Harper A. J.; Shanks E. A.; Carter G.; O’Neill M. J.; Murray T. K.; Eastwood B. J.; Schaus J. M.; Beck J. P.; Hao J.; Witkin J. M.; Li X.; Chernet E.; Katner J. S.; Wang H.; Ryder J. W.; Masquelin M. E.; Thompson L. K.; Love P. L.; Maren D. L.; Falcone J. F.; Menezes M. M.; Zhang L.; Yang C. R.; Svensson K. A. Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders. Neuropharmacology 2018, 128, 351–365. 10.1016/j.neuropharm.2017.10.032. - DOI - PubMed

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[1] Changeux J. P.; Christopoulos A. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell 2016, 166, 1084–1102. 10.1016/j.cell.2016.08.015. - DOI - PubMed

[2] Changeux J. P.; Christopoulos A. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell 2016, 166, 1084–1102. 10.1016/j.cell.2016.08.015. - DOI - PubMed

[3] Johnstone S.; Albert J. S. Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective. Bioorg. Med. Chem. Lett. 2017, 27, 2239–2258. 10.1016/j.bmcl.2017.03.084. - DOI - PubMed

[4] Johnstone S.; Albert J. S. Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective. Bioorg. Med. Chem. Lett. 2017, 27, 2239–2258. 10.1016/j.bmcl.2017.03.084. - DOI - PubMed

[5] Nussinov R.; Tsai C. J.; Csermely P. Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol. Sci. 2011, 32, 686–693. 10.1016/j.tips.2011.08.004. - DOI - PMC - PubMed

[6] Nussinov R.; Tsai C. J.; Csermely P. Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol. Sci. 2011, 32, 686–693. 10.1016/j.tips.2011.08.004. - DOI - PMC - PubMed

[7] Foster D. J.; Conn P. J. Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders. Neuron 2017, 94, 431–446. 10.1016/j.neuron.2017.03.016. - DOI - PMC - PubMed

[8] Foster D. J.; Conn P. J. Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders. Neuron 2017, 94, 431–446. 10.1016/j.neuron.2017.03.016. - DOI - PMC - PubMed

[9] Bruns R. F.; Mitchell S. N.; Wafford K. A.; Harper A. J.; Shanks E. A.; Carter G.; O’Neill M. J.; Murray T. K.; Eastwood B. J.; Schaus J. M.; Beck J. P.; Hao J.; Witkin J. M.; Li X.; Chernet E.; Katner J. S.; Wang H.; Ryder J. W.; Masquelin M. E.; Thompson L. K.; Love P. L.; Maren D. L.; Falcone J. F.; Menezes M. M.; Zhang L.; Yang C. R.; Svensson K. A. Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders. Neuropharmacology 2018, 128, 351–365. 10.1016/j.neuropharm.2017.10.032. - DOI - PubMed

[10] Bruns R. F.; Mitchell S. N.; Wafford K. A.; Harper A. J.; Shanks E. A.; Carter G.; O’Neill M. J.; Murray T. K.; Eastwood B. J.; Schaus J. M.; Beck J. P.; Hao J.; Witkin J. M.; Li X.; Chernet E.; Katner J. S.; Wang H.; Ryder J. W.; Masquelin M. E.; Thompson L. K.; Love P. L.; Maren D. L.; Falcone J. F.; Menezes M. M.; Zhang L.; Yang C. R.; Svensson K. A. Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders. Neuropharmacology 2018, 128, 351–365. 10.1016/j.neuropharm.2017.10.032. - DOI - PubMed

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Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders

Affiliations

Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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