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Article

Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities

1
Department of Physiology, 567 Wilson Road, Room 2201 Biomedical and Physical Sciences Building, Michigan State University, East Lansing, MI 48824, USA
2
Centre for Structural Systems Biology (CSSB), Notkestraße 85, 22607 Hamburg, Germany
3
Forschungszentrum Juelich GmbH, ICS-6, 52425 Juelich, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(17), 4137; https://doi.org/10.3390/ijms20174137
Received: 18 June 2019 / Revised: 7 August 2019 / Accepted: 22 August 2019 / Published: 24 August 2019
(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems)
Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action. View Full-Text
Keywords: coevolution; interactome; opiate receptors; adrenergic receptors; opioids; enhancement; tachyphylaxis; fade; prevention; reversal; drug development; combination drugs; linked compounds; tethered drugs coevolution; interactome; opiate receptors; adrenergic receptors; opioids; enhancement; tachyphylaxis; fade; prevention; reversal; drug development; combination drugs; linked compounds; tethered drugs
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MDPI and ACS Style

Root-Bernstein, R.; Churchill, B.; Turke, M.; Tiruttani Subhramanyam, U.K.; Labahn, J. Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities. Int. J. Mol. Sci. 2019, 20, 4137. https://doi.org/10.3390/ijms20174137

AMA Style

Root-Bernstein R, Churchill B, Turke M, Tiruttani Subhramanyam UK, Labahn J. Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities. International Journal of Molecular Sciences. 2019; 20(17):4137. https://doi.org/10.3390/ijms20174137

Chicago/Turabian Style

Root-Bernstein, Robert, Beth Churchill, Miah Turke, Udaya K. Tiruttani Subhramanyam, and Joerg Labahn. 2019. "Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities" International Journal of Molecular Sciences 20, no. 17: 4137. https://doi.org/10.3390/ijms20174137

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