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.
|Titolo:||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|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||11-giu-2020|
|Data ahead of print / Data di stampa:||mag-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acs.jmedchem.9b02100|
|Appare nelle tipologie:||01 - Articolo su periodico|