دورية أكاديمية
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
| العنوان: | 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 |
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| المؤلفون: | Del Bello F, Bonifazi A, Giorgioni G, Piergentili A, Sabbieti MG, Agas D, Dell'Aera M, Matucci R, Górecki M, Pescitelli G, Vistoli G, Quaglia W. |
| المساهمون: | Del Bello, F, Bonifazi, A, Giorgioni, G, Piergentili, A, Sabbieti, Mg, Agas, D, Dell'Aera, M, Matucci, R, Górecki, M, Pescitelli, G, Vistoli, G, Quaglia, W. |
| سنة النشر: | 2020 |
| المجموعة: | CAMPUS Pubblicazioni Scientifiche Unicam (Università di Camerino) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/32374602; info:eu-repo/semantics/altIdentifier/wos/WOS:000541741100008; volume:63; issue:11; firstpage:5763; lastpage:5782; numberofpages:20; journal:JOURNAL OF MEDICINAL CHEMISTRY; http://hdl.handle.net/11581/448566Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85086347001 |
| DOI: | 10.1021/acs.jmedchem.9b02100 |
| الإتاحة: | https://doi.org/10.1021/acs.jmedchem.9b02100Test http://hdl.handle.net/11581/448566Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.DB37BD3A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.9b02100 |
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