Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain alpha 9 subunits, probably in combination with alpha 10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic anti-inflammatory system (CAS), which has also been associated with alpha 7 nAChR. Both alpha 7- and alpha 9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to alpha-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of alpha 7 with CAS led to the development of numerous new ligands, variously characterized as alpha 7 agonists, partial agonists, or silent agonists that desensitized alpha 7 receptors without activation. Subsequent reinvestigation of one such family of alpha 7 ligands based on an N,N-diethyl-N '-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for alpha 9. In this paper, we characterize the alpha 9/alpha 10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of alpha 9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an alpha 9 antagonist, permitting an in silico model of alpha 9 antagonism to be developed. The alpha 9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.

New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold / C. Dallanoce, K. Richter, C. Stokes, C. Papotto, H. Andleeb, G.A. Thakur, A. Kerr, V. Grau, R.L. Papke. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 15:4(2024 Feb 21), pp. 827-843. [10.1021/acschemneuro.3c00720]

New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold

C. Dallanoce
Primo
;
C. Papotto;
2024

Abstract

Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain alpha 9 subunits, probably in combination with alpha 10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic anti-inflammatory system (CAS), which has also been associated with alpha 7 nAChR. Both alpha 7- and alpha 9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to alpha-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of alpha 7 with CAS led to the development of numerous new ligands, variously characterized as alpha 7 agonists, partial agonists, or silent agonists that desensitized alpha 7 receptors without activation. Subsequent reinvestigation of one such family of alpha 7 ligands based on an N,N-diethyl-N '-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for alpha 9. In this paper, we characterize the alpha 9/alpha 10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of alpha 9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an alpha 9 antagonist, permitting an in silico model of alpha 9 antagonism to be developed. The alpha 9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.
drug development; hearing; inflammation; nicotinic; pharmacology; voltage clamp;;
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
Settore CHEM-07/A - Chimica farmaceutica
Settore BIOS-11/A - Farmacologia
21-feb-2024
9-feb-2024
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1034116
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