title: Stereoselective behavior of the functional diltiazem analogue 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a new L-type calcium channel blocker.
abstract: We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(+)/S-(-). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity.
authors.affiliation: Dipartimento di Chimica, Universita degli Studi di Perugia, 06123 Perugia, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.forename: Francesco
authors.initials: F
authors.lastname: Gasparrini
authors.forename: Alessia
authors.initials: A
authors.lastname: Ciogli
authors.forename: Claudio
authors.initials: C
authors.lastname: Villani
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Devlin
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C545537:1-((4-chlorophenyl)sulfonyl)-2-(2-thienyl)pyrrolidine; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011759:Pyrrolidines; D013449:Sulfonamides; D004110:Diltiazem