Synthesis, affinity profile and functional activity of potent chiral muscarinic antagonists with a pyrrolidinylfuran structure.
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.
Scapecchi
Serena
S
Dipartimento di Scienze Farmaceutiche, Universita di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. serena.scapecchi@unifi.it
Nesi
Marta
M
Matucci
Rosanna
R
Bellucci
Cristina
C
Buccioni
Michela
M
Dei
Silvia
S
Guandalini
Luca
L
Manetti
Dina
D
Martelli
Cecilia
C
Martini
Elisabetta
E
Marucci
Gabriella
G
Orlandi
Francesca
F
Romanelli
Maria Novella
MN
Teodori
Elisabetta
E
Cirilli
Roberto
R
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
D005663:Furans; D018727:Muscarinic Antagonists; D011758:Pyrroles; D011976:Receptors, Muscarinic