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New Modalities in Drug Therapy: Modifying Ongoing Chemical Conversations in the Brain Terry Kenakin Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516, United States ABSTRACT: The modification of ongoing chemical signaling in the brain through allosteric modification of seven transmembrane receptors offers a wealth of diverse beneficial outcomes in drug therapy. Specifically, biased agonism can emphasize beneficial signals and de-emphasize harmful signals thus increasing the effectiveness of agonists and opening up new vistas for previously precluded drug targets. In addition, the modification of natural agonism through positive and negative allostery can provide useful rejuvenation of failing systems.
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This leads to a very useful and potentially exploitable therapeutic property whereby the reactivity of the receptor may only be modulated, not completed activated or inactivated, by the allosteric molecule. Thus, subtle increases or decreases of ongoing activity may be achieved. The second property relates to the molecular mechanism of allosterism, namely the fact that allosteric interactions occur because of changes in the tertiary conformation of the receptor. There are no systematic rules to dictate that the effect of a change in shape toward one molecule (referred to as a “probe”) interacting with the receptor will be identical to the effect of that modification on another probe (agonist) interacting with the same receptor. These properties of saturation of effect and probe dependence are extremely important in the determination of the activity of the new allosteric molecules relevant to CNS therapy. Allosteric systems have the advantage of providing a wide range of controls on complex systems. In fact, allosteric systems have been compared to complex neural networks in the brain.1 This added texture in control results from the dual inputs to an allosteric system, i.e., an allosteric molecule modifies the signal to another molecule thus the total output of the system depends on a wider range of inputs (namely, the relative concentrations of and cooperativity factors between the two cobinding molecules). Probe dependence adds yet another dimension to cobinding diversity in signaling. Specifically, receptors that are pleiotropically coupled to multiple signaling pathways and also that have multiple natural agonists have a tremendous capability for diverse signaling due to biased signaling (vide infra) resulting from allosteric probe dependence. Thus, allosteric control of 7TM receptors, either through synthetic biased agonists or allosteric modulators, offers new vistas for CNS therapies.
harmacology is the chemical control of physiology; drug therapy usually achieves this through the insertion of synthetic molecules into ongoing physiological processes and the outcome most often is initiation or cessation of chemical signals. A more subtle control can be achieved through the modification of the myriad ongoing chemical conversations already being conducted in the human body; this paper will discuss such modifications in the central nervous system (CNS) through ubiquitous biological drug targets, namely, seven transmembrane receptors (7TMRs- also known as GPCRs for G protein coupled receptors). The subtle modification of 7TMR function occurs through a mechanism called allosterism where a molecule binds to its own site on the target to modify its reactivity toward the other molecules interacting with it. 7TMRs are nature’s prototypical allosteric proteins since their sole function is to bind chemical messenger molecules in the extracellular space, change their shape in response to that interaction and subsequently modify their interaction with cytosolic molecules controlling cell signaling. The fact that 7TMRs have a range of interchangeable tertiary conformations leads to the condition that binding to 7TMRs necessarily leads to an alteration in the cellular array of conformations (termed an “ensemble”) presented to the cell, i.e., binding is not a passive process. This being the case, allosteric molecules readily modify the reactivity of 7TMRs to signaling proteins and cytosolic chemical messengers alike and this modification can be exploited therapeutically. Everything the receptor does is allosteric in that all molecules binding to it simply modify its’ reactivity to another molecule; this modified signaling can be described by an allosteric vector. If the vector is oriented to the natural agonist binding site from the allosteric modulator binding site then this molecule modifies the signaling of the natural endogenous agonist, referred to as a “guest”, binding to the receptor. Allosteric vectors oriented along the plane of the membrane describe receptor hetero- and homodimerization and vectors directed toward the cytosol are agonism. As a preface to this discussion, two important features of allosterism should be highlighted: (1) saturation of effect and (2) probe dependence. The first relates to the fact that allosteric effects (which can lead to increased or decreased receptor signaling) are limited in that their concentration dependence ceases when the allosteric site is fully occupied. © XXXX American Chemical Society
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INTRACELLULAR VECTORS: AGONISM AND BIASED SIGNALING Agonism is an allosteric enhancement of an interaction of the receptor with a cytosolic signaling protein. The availability of Received: September 28, 2016 Accepted: October 3, 2016
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DOI: 10.1021/acschemneuro.6b00330 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
In general, allosteric molecules offer great potential to modify CNS signaling for therapeutic advantage and are becoming an increasing presence in new drug discovery.7 This is because of the increasing utilization of functional assays (as opposed to the more steric modality of binding) in high-throughput screening; more allosteric molecules are being found in the initial stages of discovery. The hope is that this revolution in screening will, in turn, lead to a comparable revolution in CNS drug therapy.
functional assays to separately measure agonist-induced activation, for pleiotropically coupled receptors, has shown that not all agonists activate all signaling pathways in a uniform manner, i.e. some agonists are “biased” in that they selectively activate some pathways at the expense of others. Biased signaling is a natural fine control of physiological signaling; for example natural peptide opioid agonists are selectively biased toward cyclic AMP, extracellular signal-regulated kinase 1 and 2 phosphorylation, β-arrestin1/2 recruitment and receptor trafficking.2 The mechanism for this phenomenon is no more than probe dependent allostery in that the interaction of two separate probes of the receptor, i.e. G protein and β-arrestin, can be different due to allosteric probe dependence with the outcome that one of those pathways is activated more than the other. When built into synthetic ligands signaling bias can be beneficial for three general reasons:3 (1) Bias may emphasize a beneficial signal, (2) bias may de-emphasize a harmful signal, and (3) bias may de-emphasize a harmful signal and also block the natural signaling system from producing that same signal. Since most GPCRs are pleiotropically coupled to multiple signaling pathways in cells, the way in which cells mix these signals for an overall cellular response dictates the “quality” of efficacy of a given agonist. Thus, these qualities of efficacy can be modified through the action of biased agonists and ligands of different phenotypic efficacy quality can be directed toward drug therapy. Biased agonism also offers new therapeutic opportunities to exploit targets previously thought to be precluded from consideration as therapeutic targets. For example, κ-opioid agonism is involved in the modulation of cognition, reward, mood, and perception, theoretically making these molecules possibly useful as antidepressants and anxiolytics in affective disorders, drug addiction, and psychotic disorders. However, κopioid agonists also produce serious dysphoria, thereby precluding their application to these therapies. Biased κ-opioid agonists may circumvent these limitations by reducing dysphoric effects and emphasizing beneficial effects.4
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AUTHOR INFORMATION
Notes
The author declares no competing financial interest.
REFERENCES
(1) Nussinov, R., Tsai, C. J., and Ma, B. (2013) The underappreciated role of allostery in the cellular network. Annu. Rev. Biophys. 42, 169−189. (2) Thompson, G. L., Lane, J. R., Coudrat, T., Sexton, P. M., Christopoulos, A., and Canals, M. (2015) Biased agonism of endogenous opioid peptides at the μ-opioid receptor. Mol. Pharmacol. 88, 335−346. (3) Kenakin, T. P. (2015) The Effective Application of Biased Signaling to New Drug Discovery. Mol. Pharmacol. 88, 1055−1061. (4) White, K. L., Scopton, A. P., Rives, M.-L., Bikbulatov, R. V., Polepally, P. R., Brown, P. J., Kenakin, T., Javitch, J. A., Zjawiony, J. K., and Roth, B. L. (2014) Identification of novel functionally selective κ− opioid receptor scaffolds. Mol. Pharmacol. 85, 83−90. (5) Kenakin, T. P. (2015) The Gaddum Memorial Lecture 2014: Receptors as an evolving concept: From switches to biased microprocessors. Br. J. Pharmacol. 172, 4238−4253. (6) Leach, K., Davey, A. E., Felder, C. C., Sexton, P. M., and Christopoulos, A. (2011) The Role of Transmembrane Domain 3 in the Actions of Orthosteric, Allosteric, and Atypical Agonists of the M4Muscarinic Acetylcholine Receptor. Mol. Pharmacol. 79, 855−865. (7) Conn, P. J., Christopoulos, A., and Lindsley, C. W. (2009) Allosteric modulators of GPCRs:novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discovery 8, 41−54.
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GUEST ALLOSTERY AND INDUCED-BIAS Allosteric molecules that modify ongoing interactions of 7TMRs with their natural agonist(s) in the brain offer an even richer array of therapeutic possibilities. Such molecules can either decrease signaling (negative allosteric modulators, NAMs) or increase response (positive allosteric modulators, PAMs). While NAMs function as simple antagonists, they can come with unique properties that set them apart from standard orthosteric competitive antagonists. For instance, for NAMs that modulate but not completely block response, there can be dissociation of intensity of effect and duration of effect that can prevent overdose and increase duration of action in vivo. In addition, the permissive nature of both NAMs and PAMs introduces the possibility of induced bias into natural signaling thereby changing the very quality of natural signaling.5 Therapeutic PAMs offer the promise of revitalizing pathologically run-down signaling systems (i.e., Alzheimer’s disease) through potentiation of natural agonist affinity and more notably, efficacy. This latter effect can be quite striking; for example, the D1123.32E mutation in the muscarinic M4 receptor renders it unresponsive to acetylcholine yet the PAM LY2033298 completely restores acetylcholine responsiveness.6 PAM potentiation of physiological effect also has the added advantage of preserving the natural physiological patterns naturally encoded in brain neural function. B
DOI: 10.1021/acschemneuro.6b00330 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
