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Bioorg Med Chem Lett. 2014 Aug 1;24(15):3255-9. doi: 10.1016/j.bmcl.2014.06.020. Epub 2014 Jun 14.

Mode of interaction of 1,4-dioxane agonists at the M2 and M3 muscarinic receptor orthosteric sites.

Author information

1
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
2
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
3
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
4
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze, Viale G. Pieraccini 6, 50139 Firenze, Italy.
5
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: alessandro.piergentili@unicam.it.
6
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. Electronic address: giulio.vistoli@unimi.it.

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 human M2 and rat M3 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.

KEYWORDS:

1,4-Dioxane nucleus; Acetylcholine muscarinic receptors; Docking studies; Muscarinic agonists

PMID:
24980056
DOI:
10.1016/j.bmcl.2014.06.020
[Indexed for MEDLINE]

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