%0 Journal Article
%T On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study
%A Anna Iuliano
%A Gennaro Pescitelli
%A Marcin G¨®recki
%A Valerio Zullo
%J Archive of "Pharmaceuticals".
%D 2019
%R 10.3390/ph12010021
%X Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way
%K absolute configuration
%K drug enantiomers
%K circular dichroism calculations
%K conformational analysis
%K variable-temperature CD
%K solvent dependent CD
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469158/