The methyl group in cis stereochemical relationship with the basic chain of all pentatomic cyclic analogues of ACh is crucial for the agonist activity at mAChR. Among these only cevimeline (1) is employed in the treatment of xerostomia associated with Sjögren’s syndrome. Here we demonstrated that, unlike 1,3-dioxolane derivatives, in the 1,4-dioxane series the methyl group is not essential for the activation of mAChR subtypes. Docking studies, using the crystal structures of humanM2 and ratM3 receptors, demonstrated that the 5-methylene group of the 1,4-dioxane nucleus of compound 10 occupies the same lipophilic pocket as the methyl group of the 1,3-dioxolane 4.
Mode of interaction of 1,4-dioxane agonists at the M2 and M3 muscarinic receptor orthosteric sites / Del Bello, F; Bonifazi, A; Quaglia, W; Mazzolari, A; Barocelli, Elisabetta; Bertoni, Simona; Matucci, R; Nesi, M; Piergentili, A; Vistoli, G.. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 24:15(2014), pp. 3255-3259. [10.1016/j.bmcl.2014.06.020]
Mode of interaction of 1,4-dioxane agonists at the M2 and M3 muscarinic receptor orthosteric sites.
BAROCELLI, Elisabetta;BERTONI, Simona;
2014-01-01
Abstract
The methyl group in cis stereochemical relationship with the basic chain of all pentatomic cyclic analogues of ACh is crucial for the agonist activity at mAChR. Among these only cevimeline (1) is employed in the treatment of xerostomia associated with Sjögren’s syndrome. Here we demonstrated that, unlike 1,3-dioxolane derivatives, in the 1,4-dioxane series the methyl group is not essential for the activation of mAChR subtypes. Docking studies, using the crystal structures of humanM2 and ratM3 receptors, demonstrated that the 5-methylene group of the 1,4-dioxane nucleus of compound 10 occupies the same lipophilic pocket as the methyl group of the 1,3-dioxolane 4.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
