A Reappraisal of the Stereoselective Metabolism of Nicotine to Nicotine-l'-N-oxide

Abstract

1. The cis and trans 1′-N-oxide metabolites of (2′R)-(+)-nicotine have the absolute configuration (1′S; 2′R) and (l'R; 2′R), respectively, and not the reverse as previously published.

2. Reinterpretation of metabolic data in the light of this reassignment reveals that N-oxidation of nicotine leads preferentially to the (l'R)-N-oxide, with little dependence on the configuration of the 2′-centre.

3. It is proposed that (2′S)-(—)-nicotine and (2′R)-(+)-nicotine bind to the same enzymic site by two distinct modes of binding; each of these modes involves the more basic centre (in this case the pyrrolidine ring) as the governing binding moiety.