A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved.

Novel potent muscarinic receptor antagonists : investigation on the nature of lipophilic substituents in the 5- and/or 6-positions of the 1,4-dioxane nucleus / F. Del Bello, A. Bonifazi, G. Giorgioni, A. Piergentili, M.G. Sabbieti, D. Agas, M. Dell'Aera, R. Matucci, M. Górecki, G. Pescitelli, G. Vistoli, W. Quaglia. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:11(2020 Jun 11), pp. 5763-5782. [10.1021/acs.jmedchem.9b02100]

Novel potent muscarinic receptor antagonists : investigation on the nature of lipophilic substituents in the 5- and/or 6-positions of the 1,4-dioxane nucleus

G. Vistoli;
2020

Abstract

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved.
Settore CHIM/08 - Chimica Farmaceutica
11-giu-2020
mag-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/739731
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