Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus
Abstract
Chronic tinnitus is characterized by neuroplastic changes of the auditory cortex. A promising method for therapy of chronic tinnitus is vagus nerve stimulation (VNS) combined with auditory stimulation. The principle of VNS is reversal of pathological neuroplastic changes of the auditory cortex toward physiological neural activity and synchronicity. The VNS mechanism of action in chronic tinnitus patients is prevailingly through the muscarinic neuromodulation of the auditory cortex by the activation of nc. basalis Meynerti. The aim of this study is to propose potential pharmaceutics which may improve the neuromodulatory effects of VNS. The working hypothesis is that M1 receptors have a dominant role in the neural plasticity of the auditory cortex. We propose that allosteric agonists of the muscarinic receptor type 1 (M1) receptor could improve specificity and selectivity of the neuromodulatory effect of VNS on the auditory cortex of chronic tinnitus patients even in the circumstances of... lower acetylcholine brain concentration. This intervention would also reinforce the re-learning process of tinnitus (sub) networks by acting on cholinergic memory and learning mechanisms. We performed in silico screening of drug space using the EIIP/AQVN filter and selected 50 drugs as candidates for allosteric modulators of muscarinic receptors. Further filtering of these compounds by means of 3D QSAR and docking revealed 3 approved drugs-bromazepam, estazolam and flumazenil as the most promising candidates for combined chronic tinnitus therapy. These drugs should be further evaluated by biological tests and clinical trials.
Keywords:
tnnitus / muscarinic allosteric agonists / M1 receptor / vagus nerve stimulation / in silicoanalysis / information spectrum methodSource:
Frontiers in Neuroscience, 2017, 11, 636-Funding / projects:
- An integral study to identify the regional genetic and environmental risk factors for the common noncommunicable diseases in the human population of Serbia - INGEMA_S (RS-41028)
- Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-173001)
- MRC Institute of Hearing Research Early Career Award
DOI: 10.3389/fnins.2017.00636
ISSN: 1662-453X
PubMed: 29184482
WoS: 000415067100001
Scopus: 2-s2.0-85034053507
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VinčaTY - JOUR AU - Bojić, Tijana AU - Perović, Vladimir R. AU - Senćanski, Milan V. AU - Glišić, Sanja PY - 2017 UR - https://vinar.vin.bg.ac.rs/handle/123456789/1823 AB - Chronic tinnitus is characterized by neuroplastic changes of the auditory cortex. A promising method for therapy of chronic tinnitus is vagus nerve stimulation (VNS) combined with auditory stimulation. The principle of VNS is reversal of pathological neuroplastic changes of the auditory cortex toward physiological neural activity and synchronicity. The VNS mechanism of action in chronic tinnitus patients is prevailingly through the muscarinic neuromodulation of the auditory cortex by the activation of nc. basalis Meynerti. The aim of this study is to propose potential pharmaceutics which may improve the neuromodulatory effects of VNS. The working hypothesis is that M1 receptors have a dominant role in the neural plasticity of the auditory cortex. We propose that allosteric agonists of the muscarinic receptor type 1 (M1) receptor could improve specificity and selectivity of the neuromodulatory effect of VNS on the auditory cortex of chronic tinnitus patients even in the circumstances of lower acetylcholine brain concentration. This intervention would also reinforce the re-learning process of tinnitus (sub) networks by acting on cholinergic memory and learning mechanisms. We performed in silico screening of drug space using the EIIP/AQVN filter and selected 50 drugs as candidates for allosteric modulators of muscarinic receptors. Further filtering of these compounds by means of 3D QSAR and docking revealed 3 approved drugs-bromazepam, estazolam and flumazenil as the most promising candidates for combined chronic tinnitus therapy. These drugs should be further evaluated by biological tests and clinical trials. T2 - Frontiers in Neuroscience T1 - Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus VL - 11 SP - 636 DO - 10.3389/fnins.2017.00636 ER -
@article{ author = "Bojić, Tijana and Perović, Vladimir R. and Senćanski, Milan V. and Glišić, Sanja", year = "2017", abstract = "Chronic tinnitus is characterized by neuroplastic changes of the auditory cortex. A promising method for therapy of chronic tinnitus is vagus nerve stimulation (VNS) combined with auditory stimulation. The principle of VNS is reversal of pathological neuroplastic changes of the auditory cortex toward physiological neural activity and synchronicity. The VNS mechanism of action in chronic tinnitus patients is prevailingly through the muscarinic neuromodulation of the auditory cortex by the activation of nc. basalis Meynerti. The aim of this study is to propose potential pharmaceutics which may improve the neuromodulatory effects of VNS. The working hypothesis is that M1 receptors have a dominant role in the neural plasticity of the auditory cortex. We propose that allosteric agonists of the muscarinic receptor type 1 (M1) receptor could improve specificity and selectivity of the neuromodulatory effect of VNS on the auditory cortex of chronic tinnitus patients even in the circumstances of lower acetylcholine brain concentration. This intervention would also reinforce the re-learning process of tinnitus (sub) networks by acting on cholinergic memory and learning mechanisms. We performed in silico screening of drug space using the EIIP/AQVN filter and selected 50 drugs as candidates for allosteric modulators of muscarinic receptors. Further filtering of these compounds by means of 3D QSAR and docking revealed 3 approved drugs-bromazepam, estazolam and flumazenil as the most promising candidates for combined chronic tinnitus therapy. These drugs should be further evaluated by biological tests and clinical trials.", journal = "Frontiers in Neuroscience", title = "Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus", volume = "11", pages = "636", doi = "10.3389/fnins.2017.00636" }
Bojić, T., Perović, V. R., Senćanski, M. V.,& Glišić, S.. (2017). Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus. in Frontiers in Neuroscience, 11, 636. https://doi.org/10.3389/fnins.2017.00636
Bojić T, Perović VR, Senćanski MV, Glišić S. Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus. in Frontiers in Neuroscience. 2017;11:636. doi:10.3389/fnins.2017.00636 .
Bojić, Tijana, Perović, Vladimir R., Senćanski, Milan V., Glišić, Sanja, "Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in ChronicTinnitus" in Frontiers in Neuroscience, 11 (2017):636, https://doi.org/10.3389/fnins.2017.00636 . .