Stereoselective behavior of the functional diltiazem analogue 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a new L-type calcium channel blocker.
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.
Carosati
Emanuele
E
Dipartimento di Chimica, Universita degli Studi di Perugia, 06123 Perugia, Italy.
Budriesi
Roberta
R
Ioan
Pierfranco
P
Cruciani
Gabriele
G
Fusi
Fabio
F
Frosini
Maria
M
Saponara
Simona
S
Gasparrini
Francesco
F
Ciogli
Alessia
A
Villani
Claudio
C
Stephens
Philip J
PJ
Devlin
Frank J
FJ
Spinelli
Domenico
D
Chiarini
Alberto
A
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
C545537:1-((4-chlorophenyl)sulfonyl)-2-(2-thienyl)pyrrolidine; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011759:Pyrrolidines; D013449:Sulfonamides; D004110:Diltiazem