Synthesis and Biological Evaluation of Novel MB327 Analogs as Resensitizers for Desensitized Nicotinic Acetylcholine Receptors after Intoxication with Nerve Agents-Reference-Cited by-同舟云学术

Synthesis and Biological Evaluation of Novel MB327 Analogs as Resensitizers for Desensitized Nicotinic Acetylcholine Receptors after Intoxication with Nerve Agents

Published:2024-02-12 Issue: Volume: Page:
ISSN:
Container-title:
language:
Short-container-title:

Author:

Bernauer Tamara^ORCID,Nitsche Valentin^ORCID,Kaiser Jesko^ORCID,Gertzen Christoph G.W.^ORCID,Höfner Georg^ORCID,Niessen Karin V.^ORCID,Seeger Thomas^ORCID,Steinritz Dirk^ORCID,Worek Franz^ORCID,Gohlke Holger^ORCID,Wanner Klaus T.^ORCID,Paintner Franz F.^ORCID

Abstract

AbstractPoisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means ofin silicostudies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising 4-aminopyridinium ion-substituted MB327 analogs (PTM0056, PTM0062 and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new 4-aminopyridinium ion-substituted analogs of the aforementioned compounds (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute energetically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.

Publisher

Cold Spring Harbor Laboratory

Reference48 articles.

1. Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents

2. AmberTools

3. The Amber biomolecular simulation programs

4. Case, D.A. , H.M., A., Belfon, K. , Ben-Shalom, I.Y. , Berryman, J.T. , Brozell, S.R. , Cerutti, D.S. , Cheatham, T.E., 3rd , Cisneros, G.A. , Cruzeiro, V.W.D. , Darden, T.A. , Duke, R.E. , Giambasu, G. , Gilson, M.K. , Gohlke, H. , Goetz, A.W. , Harris, R. , Izadi, S. , Izmailov, S.A. , Kasavajhala, K. , Kaymak, M.C. , King, E. , Kovalenko, A. , Kurtzmann, T. , Lee, T.S. , Le Grand, S. , Li, P. , Lin, C. , Liu, J. , Luchko, T. , Luo, R. , Machado, M. , Man, V. , Manathunga, M. , Merz, K.M. , Miao, Y. , Mikhailovskii, O. , Monard, G. , Nguyen, H. , O’Hearn, K.A. , Onufriev, A. , Pan, F. , Pantano, S. , Qi, R. , Rahnamoun, A. , Roe, D.R. , Roitberg, A. , Sagui, E. , Schott-Verdugo, S. , Shajan, A. , Shen, J. , Simmerling, C.L. , Skrynnikov, N.R. , Smith, J. , Swails, J. , Walker, R.C. , Wang, J. , Wang, J. , Wei, H. , Wolf, R.M. , Wu, X. , Xiong, Y. , Xue, Y. , York, D.M. , Zhao, S. , Kollmann, P.A. , 2022. Amber 2022. vol. Amber 2022. University of California, San Francisco.

5. Chemical Computing Group , U., 2020. Molecular Operating Environment (MOE). vol. 2019.01, 1010 Sehrbooke St. West, Suite #910, Montreal, QC, Canada, H3A, 2R7.