From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Jul 14

PMID 35834819

Authors

Francesco Bavo

Marco Pallavicini

Susanna Pucci

Rebecca Appiani

Alessandro Giraudo

Brek Eaton

Linda Lucero

Cecilia Gotti

Milena Moretti

Paul Whiteaker

Cristiano Bolchi

Affiliations

Soon will be listed here.

Abstract

Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest for pain treatment alternative to opioids. Nonpeptidic small molecules selectively acting as α9*-nAChRs antagonists still remain an unattained goal. Here, through modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known α7- and α9*-nAChRs antagonist, into some selective antagonists of human α9*-nAChR. Among these, the compound with cyclohexyldimethylammonium head () stands out for having no α7-nAChR agonist or antagonist effect along with very low affinity at both α7- and α3β4-nAChRs. At supra-micromolar concentrations, and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very brief response, followed by rebound current once the application is stopped and the channel is disengaged. The small or null postapplication activity of ACh seems to be related to the slow recovery of the rebound current.

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References

Zoli M, Pucci S, Vilella A, Gotti C . Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors. Curr Neuropharmacol. 2017; 16(4):338-349. PMC: 6018187. DOI: 10.2174/1570159X15666170912110450. View

Hone A, Whiteaker P, Christensen S, Xiao Y, Meyer E, McIntosh J . A novel fluorescent alpha-conotoxin for the study of alpha7 nicotinic acetylcholine receptors. J Neurochem. 2009; 111(1):80-9. PMC: 2749889. DOI: 10.1111/j.1471-4159.2009.06299.x. View

Cavallini G, MASSARANI E . [Further research on stilbene and diphenylethane derivatives; new synthetic antinicotinics. III..]. Farmaco Sci. 1954; 9(8):405-15. View

Liang J, Tae H, Xu X, Jiang T, Adams D, Yu R . Dimerization of α-Conotoxins as a Strategy to Enhance the Inhibition of the Human α7 and α9α10 Nicotinic Acetylcholine Receptors. J Med Chem. 2020; 63(6):2974-2985. DOI: 10.1021/acs.jmedchem.9b01536. View

Pucci S, Zoli M, Clementi F, Gotti C . α9-Containing Nicotinic Receptors in Cancer. Front Cell Neurosci. 2022; 15:805123. PMC: 8814915. DOI: 10.3389/fncel.2021.805123. View

Wyrzykiewicz E, Wendzonka M, Kedzia B . Synthesis and antimicrobial activity of new (E)-4-[piperidino (4'-methylpiperidino-, morpholino-) N-alkoxy]stilbenes. Eur J Med Chem. 2006; 41(4):519-25. DOI: 10.1016/j.ejmech.2005.11.010. View

Fucile S . The Distribution of Charged Amino Acid Residues and the Ca Permeability of Nicotinic Acetylcholine Receptors: A Predictive Model. Front Mol Neurosci. 2017; 10:155. PMC: 5447003. DOI: 10.3389/fnmol.2017.00155. View

Kuryatov A, Luo J, Cooper J, Lindstrom J . Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol. 2005; 68(6):1839-51. DOI: 10.1124/mol.105.012419. View

Neher E, Steinbach J . Local anaesthetics transiently block currents through single acetylcholine-receptor channels. J Physiol. 1978; 277:153-76. PMC: 1282384. DOI: 10.1113/jphysiol.1978.sp012267. View

10.

Elgoyhen A, Vetter D, Katz E, Rothlin C, Heinemann S, Boulter J . alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc Natl Acad Sci U S A. 2001; 98(6):3501-6. PMC: 30682. DOI: 10.1073/pnas.051622798. View

11.

Pedretti A, Marconi C, Bolchi C, Fumagalli L, Ferrara R, Pallavicini M . Modelling of full-length human alpha4beta2 nicotinic receptor by fragmental approach and analysis of its binding modes. Biochem Biophys Res Commun. 2008; 369(2):648-53. DOI: 10.1016/j.bbrc.2008.02.080. View

12.

Cavallini G, Mantegazza P, MASSARANI E, Tommasini R . [The ganglion-blocking activities of some alkylamine derivatives of stilbene and of biphenyl]. Farmaco Sci. 1953; 8(6):317-31. View

13.

Lukas R, Changeux J, Le Novere N, Albuquerque E, Balfour D, Berg D . International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol Rev. 1999; 51(2):397-401. View

14.

Zheng G, Zhang Z, Dowell C, Wala E, Dwoskin L, Holtman J . Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain. Bioorg Med Chem Lett. 2011; 21(8):2476-9. PMC: 3726002. DOI: 10.1016/j.bmcl.2011.02.043. View

15.

Kerr A, Tam L, Hale A, Cioroch M, Douglas G, Agkatsev S . A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor. J Pharmacol Exp Ther. 2017; 361(3):417-428. PMC: 5443320. DOI: 10.1124/jpet.116.239574. View

16.

Indurthi D, Pera E, Kim H, Chu C, McLeod M, McIntosh J . Presence of multiple binding sites on α9α10 nAChR receptors alludes to stoichiometric-dependent action of the α-conotoxin, Vc1.1. Biochem Pharmacol. 2014; 89(1):131-40. PMC: 5089836. DOI: 10.1016/j.bcp.2014.02.002. View

17.

Daina A, Michielin O, Zoete V . SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7:42717. PMC: 5335600. DOI: 10.1038/srep42717. View

18.

Kassner M, Eaton J, Tang N, Petit J, Meurice N, Yin H . High-throughput cell-based assays for identifying antagonists of multiple smoking-associated human nicotinic acetylcholine receptor subtypes. SLAS Discov. 2022; 27(1):68-76. PMC: 8816891. DOI: 10.1016/j.slasd.2021.10.001. View

19.

Bavo F, Pallavicini M, Gotti C, Appiani R, Moretti M, Colombo S . Modifications at C(5) of 2-(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 Subtype. J Med Chem. 2020; 63(24):15668-15692. DOI: 10.1021/acs.jmedchem.0c01150. View

20.

Morley B, Whiteaker P, Elgoyhen A . Commentary: Nicotinic Acetylcholine Receptor α9 and α10 Subunits Are Expressed in the Brain of Mice. Front Cell Neurosci. 2018; 12:104. PMC: 5938352. DOI: 10.3389/fncel.2018.00104. View