Synthesis and pharmacological characterization of chiral pyrrolidinylfuran derivatives: the discovery of new functionally selective muscarinic agonists.
Building on the previously and successfully applied hypothesis that stereochemical complication in the proximity of the critical cationic head of a cholinergic agonist would result in subtype selective compounds, we synthesized a series of chiral derivatives of furmethide and 5-methylfurmethide, with the aim of obtaining compounds that are useful for treating diseases derived from cholinergic receptor dysfunctions and/or useful for further characterizing subtypes of cholinergic receptors. Unlike their parent compounds, the new molecules lack nicotinic activity, being pure muscarinic ligands. While binding studies on the five cloned human muscarinic receptors showed no subtype selectivity, functional assays revealed that some of the molecules of the series are potent M 2 selective partial agonists with interesting pharmacological profiles.
Scapecchi
Serena
S
Dipartimento di Scienze Farmaceutiche, Università 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
Martini
Elisabetta
E
Marucci
Gabriella
G
Romanelli
Maria Novella
MN
Teodori
Elisabetta
E
Cirilli
Roberto
R
D000818:Animals; D016466:CHO Cells; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D011817:Rabbits; D013053:Spectrophotometry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D005663:Furans; D018721:Muscarinic Agonists; D011758:Pyrroles