Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in Chronic Tinnitus

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: M1 receptor; in silico analysis; information spectrum method; muscarinic allosteric agonists; tinnitus; vagus nerve stimulation.

Figure 1

Schematic presentation of the EIIP/AQVN criterion for selection of candidate allosteric modulators of muscarinic receptor M1. Active domain (red): AQVN (3–3.08), EIIP (0.004–0.073). Chemical space (blue) AQVN (2.40–3.30) EIIP (0.000–0.116) EIIP/AQVN domain of homologous distribution of >90% compounds from PubChem Compound Database.

Figure 2

Bromazepam in allosteric modulator binding region of M1 acetylcholine receptor, with marked aminoacids, and intermolecular interactions. Green: hydrogen bonds, purple: hydrophobic interactions.

Figure 3

Estazolam in allosteric modulator binding region of M1 acetylcholine receptor, with marked aminoacids, and intermolecular interactions. Green: hydrogen bonds, purple: hydrophobic interactions.

Figure 4

Flumazenil in allosteric modulator binding region of M1 acetylcholine receptor, with marked aminoacids, and intermolecular interactions. Green: hydrogen bonds, purple: hydrophobic interactions.