Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities
Abstract
:1. Introduction
- (1)
- (2)
- In consequence, every molecule involved in living systems interacts more or less specifically, strongly, and transiently with several others to form the chemical basis of an “interactome” [70].
- (3)
- (4)
- (5)
- Receptors for molecularly complementary ligands evolve complementary functions. For example, a homocomplementary molecule may evolve into a ligand–receptor pair, or heterocomplementary molecules may evolve so that one becomes the ligand and the other the receptor.
- (6)
- As a result of principles 1–5, compounds that are molecularly complementary will alter each other’s physiological activity, and conversely, when compounds alter each other’s physiological activity, they will be found to be molecularly complementary [77].
- (7)
2. Results
2.1. Opioid Compounds Bind to Adrenergic Compounds
2.2. Adrenergic Compounds Bind to Opioid Receptor Peptides
2.3. Epinephrine Binds to Intact Mu Opioid Receptor
3. Discussion
3.1. Summary of Observations
3.2. Ligand Complementarity and Drug Development
3.3. Proofs of Concept for Complementary Ligand Approach to Enhancer Drug Development
4. Methods
4.1. Opioid–Adrenergic Compound Binding Test Methods
4.2. Opioid Peptide Binding Test Methods
4.3. Human Mu Opioid Receptor (muOPR) Expression and Purification
4.4. Binding of Epinephrine and Opioids to muOPR Monitored by Ultraviolet Spectroscopy
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Kd (µM) @ 200 nm | M-Enk | Morph | Meth | NAL | Amph | Prop | Asc | Glucose | Ribo |
---|---|---|---|---|---|---|---|---|---|
Epinephrine HCl | 5.8/40 * | 0.3/40 * | 300 | 100 | 4.5 | 45/1000 | 90 # | >1000 | >1000 |
Norepinephrine HCl | 5.3/35 * | 0.4 * | 70 | 80 | 80 | >1000 | 110 # | >1000 | >1000 |
Dopamine | 30 * | 0.6 * | 200 | 90 | 90 | 100 | 100 | >1000 | >1000 |
L-DOPA | 70 * | >1000 * | 80 | 55 | 11 | 15 | 100 | >1000 | >1000 |
Amphetamine | 80 * | 0.1 * | 2.5 | 60 | >1000 | >1000 | >1000 | >1000 | |
Propranolol | 3.0/35 | 0.8/45 | >1000 | 90 | 90 | 160 | >1000 | 220 | |
Salbutamol | 30 | 0.3 | >1000 | 180 | 0.6 | 1.0/130 | 160 | >1000 | 50 |
Isoproterenol | 40 | 0.1 | 13 | 13 | 0.1 | 11 | 130 | >1000 | >1000 |
Phenylephrine | 30 | 0.13 | >1000 | 20 | 17 | 20 | >1000 | >1000 | >1000 |
Tyramine | 12 * | 50 | 210 | 90 | 60 | 80 | 200 | >1000 | 40 |
Octopamine | 80 * | 3.2 * | >1000 | 55 | 100 | 220 | >1000 | 30 | |
Homovanillic Acid | 80 * | >1000 * | >1000 | 85 | 1.5/90 | >1000 | >1000 | 70 | |
Tyrosine | >1000 | >1000 | 250 | 75 | 53 | 20 | 270 | >1000 | >1000 |
Phenylalanine | >1000 | >1000 | >1000 | 70 | 85 | >1000 | >1000 | 50 | |
Serotonin | 45 * | 0.7 * | 45 | 60 | >1000 | 100 | >1000 | >1000 | 7 |
Melatonin | 130 | 300 | 300 | 12 | 70 | 90 | 400 | >1000 | 150 |
Histamine | >1000 * | >1000 * | >1000 | 210 | 70 | 110 | >1000 | >1000 | >1000 |
Acetylcholine | 80 * | >1000 * | >1000 | >1000 | >1000 | >1000 | >1000 | >1000 | >1000 |
Kd (μM) @ 200 nm | Mor | Nalox | M-Enk | Epi | NorEpi | Amph | DOP | 5HT | ACh | Hist |
---|---|---|---|---|---|---|---|---|---|---|
MuOPR 38–51 | 35 | 0.5/35 | 0.15/55 | 1.2/35 | 1.4/45 | 1.3/90 | 60 | 100 | >1000 | >1000 |
MuOPR 111–122 | 50 | 0.5/38 | 0.33/80 | 1.3/40 | 1.3/40 | 1.3/100 | 65 | 100 | >1000 | >1000 |
MuOPR 121–131 | 900 | >1000 | 3.5/90 | >1000 | >1000 | >1000 | >1000 | 350 | >1000 | >1000 |
MuOPR 132–143 | 35 | 0.5/42 | 0.4 /70 | 1.4/35 | 1.4/40 | 1.1/85 | 60 | 100 | >1000 | >1000 |
MuOPR 211–226 | 30 | 1.0/45 | 1.0/65 | 1.2/40 | 1.3/45 | 1.2/90 | 65 | 90 | >1000 | >1000 |
D1DR 89–98 | 20 | 5 | 80 | 400 | 300 | 530 | 75 | >1000 | >1000 | 600 |
D1DR 170–188 | 310 | 150 | 150 | 900 | >1000 | 230 | 300 | >1000 | >1000 | >1000 |
H1HR 77–87 | 110 | 110 | 2.3/70 | 30 | 30 | 60 | 30 | 75 | >1000 | 20 |
B2AR 97–103 | 1 | 6 | 130 | 120 | 600 | 130 | 70 | 120 | >1000 | >1000 |
B2AR 175–188 | 50 | 40 | 700 | 900 | 1000 | 2.3/600 | 800 | >1000 | >1000 | >1000 |
INSR 157–166 | 60 | 200 | 100 | >1000 | 140 | 400 | >1000 | 110 | >1000 | 110 |
INSR 281–299 | >1000 | >1000 | >1000 | 200 | >1000 | >1000 | >1000 | 900 | >1000 | >1000 |
Kd @ 210 nm (μM) | Kd @ 200 nm (μM) | |
---|---|---|
Acetylcholine | >1000 | >1000 |
Histamine | >1000 | >1000 |
Ascorbic Acid (Vitamin C) | >1000 | >1000 |
Naloxone | 40 | 2.5/80 |
Methadone | 50 | 60 |
Epinephrine | 20/1000 | 30 |
Methionine-Enkephalin | 10 | 0.8/15 |
Methionine-Enkephalin + Epinephrine | 4 | <0.01/4 |
Morphine | 20 | 0.9/60 |
Morphine + Epinephrine | 6 | <0.01/0.9/9 |
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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
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 StyleRoot-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