Synthesis, affinity profile and functional activity of potent chiral muscarinic antagonists with a pyrrolidinylfuran structure.

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Scapecchi S, Nesi M, Matucci R, Bellucci C, Buccioni M, Dei S, Guandalini L, Manetti D, Martelli C, Martini E, Marucci G, Orlandi F, Romanelli MN, Teodori E, Cirilli R

Synthesis, affinity profile and functional activity of potent chiral muscarinic antagonists with a pyrrolidinylfuran structure.

J Med Chem. 2010 Jan 14;53(1):201-7. doi: 10.1021/jm901048j.

PubMed ID

19928767 [ View in PubMed

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Abstract

Starting from the structure of previously studied muscarinic agonists, characterized by a pyrrolidinylfuran scaffold, a new series of muscarinic antagonists was synthesized by substituting the 5-position of the furane cycle with bulky hydrophobic groups. Both tertiary amines and the corresponding iodomethyl derivatives were obtained and studied. All the new compounds show high affinity toward cloned human muscarinic M(1)-M(5) receptors expressed in Chinese hamster ovary (CHO) cells and behave as competitive antagonists on classical models of muscarinic receptors. The diastereoisomeric mixture of the highest affinity compound of the series was resolved into the four optical isomers by chiral HPLC. The relative and absolute configuration of the obtained compounds was established by means of a combined strategy based on X-ray crystallography and chiroptical techniques. Although generally fairly potent, the compounds showed only modest subtype selectivity, with the exception of 2a and 6a, which in functional assays presented clear-cut selectivity for the muscarinic receptors present in rabbit vas deferens.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methscopolamine bromide	Muscarinic acetylcholine receptor M1	Ki (nM)	0.324	N/A	N/A	Details
Methscopolamine bromide	Muscarinic acetylcholine receptor M2	Ki (nM)	0.178	N/A	N/A	Details
Methscopolamine bromide	Muscarinic acetylcholine receptor M3	Ki (nM)	0.135	N/A	N/A	Details