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Novel Opioid Analgesics and Side Effects Giovanna Del Vecchio, Viola Spahn, and Christoph Stein* Department of Anesthesiology and Critical Care Medicine, Charité- Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany ABSTRACT: Conventional opioids mediate analgesia as well as severe adverse effects via G-protein coupled opioid receptors (OR) in both inflamed (peripheral injured tissue) and healthy (brain, intestinal wall) environments. To exclude side effects, OR activation can be selectively achieved in damaged tissue by lowering the pKa of an opioid ligand to the acidic pH of inflammation. As a result, protonation of the ligand and consequent OR binding and activation of G-proteins is pH- and injury-specific. A novel compound (NFEPP) demonstrates the feasibility of this approach and displays blockade of pain transmission only at the peripheral site of injury, but with lack of central and gastrointestinal adverse effects. These findings suggest disease-specific receptor activation as a new strategy in drug design. KEYWORDS: Opioids, analgesia, opioid receptor, inflammation, injury
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result from inhibitory and/or indirect disinhibitory actions in the central vomiting and vestibular centers and in the gastrointestinal tract. Respiratory depression is mediated by inhibition of neuronal firing in the pre-Bötzinger complex, and different nuclei in the medulla and pons. Opioid-induced sedation apparently results from suppression of central neurons driving arousal.2 G-protein signaling can be terminated by engagement of OR with β-arrestins upon receptor phosphorylation by G-protein coupled receptor (GPCR) kinases, resulting in G-protein uncoupling, desensitization and receptor internalization/recycling (Figure 1). These events have been related to tolerance development, i.e., progressively decreasing responses with prolonged agonist administration. For example, mice lacking β-arrestin-2 did not develop tolerance to opioids, but displayed enhanced G-protein activation, analgesia, and reward.4 This stimulated investigations into selective arrestin-mediated signaling (see below).
ain treatment is a major challenge in clinical medicine and public health. Unfortunately, currently available analgesics are severely limited by adverse effects. Opioids produce sedation, apnea, nausea, addiction, and constipation mediated in brain or gut, and nonsteroidal anti-inflammatory drugs can elicit gastrointestinal ulcers, bleeding, myocardial infarction, or stroke.1 The spreading epidemic of opioid misuse and escalating death rates have prompted recent initiatives and revised guidelines for the management of pain,1 and have stimulated basic research into mechanisms of analgesic drug action.
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OPIOID RECEPTOR SIGNALING Opioid receptors (OR) are widely and differentially expressed in the central (cortex, limbic system, basal ganglia, brainstem, spinal cord) and peripheral nervous system (dorsal root ganglia, peripheral sensory and enteric neurons).2 Classic opioid agonists activate OR and induce coupling to G-proteins, which dissociate into Gα and Gβγ subunits, thereby inhibiting adenylyl cyclase and modulating ion channels. Ultimately, this results in an increase of potassium and inhibition of calcium conductance across the membrane, as well as a suppression of neurotransmitter release and an overall decrease in neuronal excitability (Figure 1). The simultaneous and synergistic modulation of multiple intracellular signaling pathways and membrane ion channels by OR confers a significant advantage over other analgesic drug targets, such as the selective blockade of individual excitatory ion channels or receptors, thus implying a much wider range of efficacy. The above events exert a net inhibitory action on pain transmission/processing at the peripheral sensory neuron and at different spinal and supraspinal centers. However, these same G-protein mediated actions modulate neuronal networks in different areas of the brain like those mediating reward/ reinforcement (ventral tegmental area, nucleus accumbens), explaining the addictive/reinforcing properties of many opioids.2 Constipation can also be ascribed to the inhibitory action of opioids, particularly on the firing/excitability of intestinal myenteric and submucosal neurons, thereby blocking, for example, the release of acetylcholine.3 Nausea and vomiting © XXXX American Chemical Society
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CENTRAL AND PERIPHERAL OR IN PAINFUL SYNDROMES A large variety of painful syndromes (e.g., surgery, arthritis, cancer, neuropathy) are driven by peripheral sensory neurons and are typically accompanied by inflammation with tissue acidosis.3,5 Under such circumstances, peripheral OR and their signaling pathways are upregulated and mediate a considerable proportion of opioid analgesia in animals and humans. Inflammatory components induce increased expression of peripheral OR at the mRNA and protein level, as well as increased centrifugal axonal transport and G-protein coupling.3 In particular, extracellular protons seem to affect the function of GPCR as well as the protonation of ligands required for binding and activation of OR (Figures 1 and 2).5 It has also been suggested that methylation-regulated gene expression and cytokines are involved in peripheral OR and opioid peptide expression, that OR trafficking to the neuronal membrane and opioid actions (e.g., inhibition of neuropeptide release, cAMP Received: May 25, 2017 Accepted: May 26, 2017
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DOI: 10.1021/acschemneuro.7b00195 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. OR-mediated intracellular signaling. The classic opioid fentanyl (pink with light blue triangles) is able to bind and activate OR (indigo) in injured and healthy tissues, because it is protonated under both conditions (pKa ca. 8). The activation of OR results in the dissociation of G-protein heterotrimers, inhibition of adenylyl cyclase (AC) by Gαi, and modulation of Ca2+ and K+ channels by Gβγ. β-arrestin binding and OR phosphorylation induce receptor internalization. The corresponding cellular effects are listed in the white boxes.
accumulation, modulation of voltage-dependent cation channels) are increased, and that the transperineurial accessibility of OR is enhanced during inflammation. Experimental evidence suggests that chronic opioid treatment does not lead to the development of tolerance at peripheral OR in the presence of injury, likely due to increased internalization and G-protein coupling of OR in the presence of endogenous opioid peptides. Thus, the continuous availability of endogenous opioids in inflamed tissue seems to be important for OR recycling and may preserve signaling of OR in peripheral sensory neurons.3
Another approach considers disease-specific GPCR activation. Current structural information on OR and ligands is limited to physiological environments (pH 7.4), therefore calling for analysis of their pathological conformations. The idea that the conditions at the site of injury (e.g., tissue acidosis) could be exploited to yield opioids devoid of side effects has been explored recently5 (Figure 1). Using computational simulations and reducing the pKa of an opioid agonist to the pH of inflamed tissue by fluorination yielded a molecule (NFEPP) whose protonation appears to be selective for the inflamed environment. As a consequence of the essential role of protonation for the binding of opioids to OR, NFEPP has been shown to selectively bind OR and activate G-proteins at low pH. The protonated ligand blocks pain transmission only at the site of injury (Figure 2). The lack of protonation of NFEPP in healthy tissue (brain, intestinal wall) explains the absence of side effects like sedation, motor impairment, conditioned place preference (addiction potential), and constipation.5 Clinical studies will have to demonstrate that this new strategy indeed results in a reduction of adverse side effects in patients.
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EMERGING DIRECTIONS AND CRITICAL EVALUATION A novel opioid analgesic should ideally retain the ability to activate G-proteins within the pain control network exclusively, therefore reducing firing and excitability of sensory neurons and selectively producing analgesia without respiratory depression, sedation, constipation or addiction potential. Unfortunately, as discussed above, many adverse effects induced by classic opioids relate to the ability of OR to activate G-proteinmediated intracellular signaling nonselectively in different areas of the central and peripheral nervous system (Figure 2). In an effort to develop opioid ligands devoid of side effects, different strategies have been pursued, including targeting peripheral OR, different receptor subtypes or β-arrestin-biased signaling.3,4 Recent advances in the crystallization of GPCRs in active and inactive states might open the way to structure-based discovery of new opioid analgesics and could help to delineate the basis of side effects and functional selectivity (biased signaling). Unfortunately, clinical studies in surgical patients receiving the biased agonist TRV130 showed similar side effects to morphine.6
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare the following competing financial interest: Christoph Stein is one of the inventors of US patent 14/239,461.
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REFERENCES
(1) Grosser, T., Woolf, C. J., and FitzGerald, G. A. (2017) Time for nonaddictive relief of pain. Science 355, 1026−1027.
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DOI: 10.1021/acschemneuro.7b00195 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 2. Novel strategy to selectively activate OR at the peripheral injury site without triggering side effects. NFEPP is designed to act only in injured conditions by modulating pKa and protonation state, a prerequisite for ligand binding and activation of OR. The ligand (purple circles) is protonated (light blue triangles around the purple circles) only in inflamed environment (red) surrounding the peripheral nerve endings (light gray). The protonated molecules bind and activate OR (dark gray), whereas the unprotonated molecules (in healthy brain and gastrointestinal wall) do not. NFEPP: (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (gray circle inset). (2) Schumacher, M. A., Basbaum, A. I., and Naidu, R. K. (2015) Opioid Agonists & Antagonists. In Basic and clinical pharmacology, 13th ed. (Katzung, B. G., and Trevor, A. J., Eds.), pp 531−551, McGraw-Hill Medical. (3) Stein, C. (2016) Opioid Receptors. Annu. Rev. Med. 67, 433−51. (4) Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., Koch, T., Evans, C. J., and Christie, M. J. (2013) Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 65, 223−54. (5) Spahn, V., Del Vecchio, G., Labuz, D., Rodriguez-Gaztelumendi, A., Massaly, N., Temp, J., Durmaz, V., Sabri, P., Reidelbach, M., Machelska, H., Weber, M., and Stein, C. (2017) A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355, 966−969. (6) Viscusi, E. R., Webster, L., Kuss, M., Daniels, S., Bolognese, J. A., Zuckerman, S., Soergel, D. G., Subach, R. A., Cook, E., and Skobieranda, F. (2016) A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain 157, 264−72.
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DOI: 10.1021/acschemneuro.7b00195 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
