Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Feb 11

PMID 36770942

Authors

Dina Manetti

Silvia Dei

Hugo R Arias

Laura Braconi

Alessio Gabellini

Elisabetta Teodori

Maria Novella Romanelli

Affiliations

Soon will be listed here.

Abstract

Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4β2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions.

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References

Papke R, Meyer E, Nutter T, Uteshev V . alpha7 receptor-selective agonists and modes of alpha7 receptor activation. Eur J Pharmacol. 2000; 393(1-3):179-95. DOI: 10.1016/s0014-2999(00)00009-1. View

Dunlop J, Lock T, Jow B, Sitzia F, Grauer S, Jow F . Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide). J Pharmacol Exp Ther. 2008; 328(3):766-76. DOI: 10.1124/jpet.108.146514. View

Chatzidaki A, Millar N . Allosteric modulation of nicotinic acetylcholine receptors. Biochem Pharmacol. 2015; 97(4):408-417. DOI: 10.1016/j.bcp.2015.07.028. View

Malysz J, Gronlien J, Anderson D, Hakerud M, Thorin-Hagene K, Ween H . In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile. J Pharmacol Exp Ther. 2009; 330(1):257-67. DOI: 10.1124/jpet.109.151886. View

Uteshev V, Meyer E, Papke R . Activation and inhibition of native neuronal alpha-bungarotoxin-sensitive nicotinic ACh receptors. Brain Res. 2002; 948(1-2):33-46. DOI: 10.1016/s0006-8993(02)02946-3. View

Taly A, Corringer P, Guedin D, Lestage P, Changeux J . Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov. 2009; 8(9):733-50. DOI: 10.1038/nrd2927. View

Arias H . Positive and negative modulation of nicotinic receptors. Adv Protein Chem Struct Biol. 2010; 80:153-203. DOI: 10.1016/B978-0-12-381264-3.00005-9. View

Mazurov A, Hauser T, Miller C . Selective alpha7 nicotinic acetylcholine receptor ligands. Curr Med Chem. 2006; 13(13):1567-84. DOI: 10.2174/092986706777442011. View

McIntosh J, Absalom N, Chebib M, Elgoyhen A, Vincler M . Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem Pharmacol. 2009; 78(7):693-702. PMC: 2739401. DOI: 10.1016/j.bcp.2009.05.020. View

10.

Papke R, Horenstein N . Therapeutic Targeting of 7 Nicotinic Acetylcholine Receptors. Pharmacol Rev. 2021; 73(3):1118-1149. PMC: 8318519. DOI: 10.1124/pharmrev.120.000097. View

11.

Sahdeo S, Wallace T, Hirakawa R, Knoflach F, Bertrand D, Maag H . Characterization of RO5126946, a Novel α7 nicotinic acetylcholine receptor-positive allosteric modulator. J Pharmacol Exp Ther. 2014; 350(2):455-68. DOI: 10.1124/jpet.113.210963. View

12.

Potasiewicz A, Holuj M, Kos T, Popik P, Arias H, Nikiforuk A . 3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats. Neuropharmacology. 2016; 113(Pt A):188-197. DOI: 10.1016/j.neuropharm.2016.10.002. View

13.

Targowska-Duda K, Budzynska B, Michalak A, Jozwiak K, Biala G, Arias H . 3-Furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic receptors, produces anxiolytic-like activity in mice. J Psychopharmacol. 2019; 33(5):558-567. DOI: 10.1177/0269881118821100. View

14.

Pismataro M, Horenstein N, Stokes C, Dallanoce C, Thakur G, Papke R . Stable desensitization of α nicotinic acetylcholine receptors by NS6740 requires interaction with S36 in the orthosteric agonist binding site. Eur J Pharmacol. 2021; 905:174179. PMC: 8478151. DOI: 10.1016/j.ejphar.2021.174179. View

15.

Zhao Y, Liu S, Zhou Y, Zhang M, Chen H, Xu H . Structural basis of human α7 nicotinic acetylcholine receptor activation. Cell Res. 2021; 31(6):713-716. PMC: 8169775. DOI: 10.1038/s41422-021-00509-6. View

16.

Yi B, Long S, Gonzalez-Cestari T, Henderson B, Pavlovicz R, Werbovetz K . Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies. Bioorg Med Chem. 2013; 21(15):4730-43. PMC: 4347880. DOI: 10.1016/j.bmc.2013.03.082. View

17.

Boffi J, Wedemeyer C, Lipovsek M, Katz E, Calvo D, Elgoyhen A . Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid. Br J Pharmacol. 2012; 168(4):954-65. PMC: 3631383. DOI: 10.1111/j.1476-5381.2012.02221.x. View

18.

Glassco W, Suchocki J, George C, Martin B, May E . Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- and (-)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-1H- pyrrolo-[3,2-h]isoquinoline, a structural analog of nicotine. J Med Chem. 1993; 36(22):3381-5. DOI: 10.1021/jm00074a019. View

19.

Quick M, Lester R . Desensitization of neuronal nicotinic receptors. J Neurobiol. 2002; 53(4):457-78. DOI: 10.1002/neu.10109. View

20.

Hsiao B, Mihalak K, Repicky S, Everhart D, Mederos A, Malhotra A . Determinants of zinc potentiation on the alpha4 subunit of neuronal nicotinic receptors. Mol Pharmacol. 2005; 69(1):27-36. DOI: 10.1124/mol.105.015164. View