title: Muscarinic subtype affinity and functional activity profile of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine and 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine derivatives.
abstract: Starting from two previously studied muscarinic full agonists, characterized by a 1,3-dioxolane ((+)-1) and a 1,3-oxathiolane ((+)-2) cycle, two new series of muscarinic ligands were designed, obtained by the steric complication of the parent compounds produced by freezing the aminoalkyl chain into a pyrrolidine ring. Both tertiary amines and the corresponding iodomethyl derivatives were synthesised and studied, and several compounds of the series which behaved as muscarinic agonists have been selected, on the basis of preliminary binding experiments on rat cortex homogenates, for the present work. Results are presented obtained from testing the affinity of the selected compounds against cloned human muscarinic receptors expressed in CHO cells, in order to evaluate subtype selectivity. Their functional activity on classical models of M1-M4 receptors, in guinea pig and rabbit tissues is also reported. With respect to parent compounds, the new molecules present some selectivity toward hm2 receptors; fair M2 selectivity is also evident in functional studies, where these compounds behave as partial agonists. Among the other compounds of the series (2S, 4'R, 2'S)-1,1-dimethyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidinium iodide (-)-3 and (2R, 5'S, 2'S)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine (+)-5 present a promising pharmacological profile. Compound (-)-3 shows modest hm2 selectivity in binding experiments but a clearcut M2 selectivity in functional tests, where it behaves as a weak antagonist on M1 and M4 subtypes, as a weak full agonist on the M3 subtype and as a potent partial agonist on M2 subtype. Tertiary amine (+)-5 presents a quite similar profile but appears more interesting since, lacking a permanent charge on the nitrogen atom, it may represent an interesting tool to study CNS muscarinic receptors. Our results confirm that sterical complication of parent compounds (+)-1 and (+)-2 produces more selective muscarinic agonists.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy. silvia.dei@unifi.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Cristina
authors.initials: C
authors.lastname: Bellucci
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Fulvio
authors.initials: F
authors.lastname: Gualtieri
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D020033:Protein Isoforms; D011759:Pyrrolidines; D011976:Receptors, Muscarinic