Enantiomers of [R,S]-thiorphan: dissociation of analgesia from enkephalinase A inhibition

The R] and S] enantiomers of the enkephalinase A inhibitor R,S]-thiorphan have been prepared by asymmetric synthesis. The S] isomer is principally responsible for the angiotensin converting enzyme inhibitory activity of R,S]-thiorphan, whereas there were only small differences in the ability of the R] and S] isomers to inhibit enkephalinase both in vivo and in vitro. In contrast, the in vivo analgesic activity of R,S]-thiorphan resided principally in the R] isomer. These data indicate a surprising dissociation of enkephalinase inhibition from analgesic activity. The fact that the two enantiomers of R,S]-thiorphan were effective inhibitors of enkephalinase, yet the R] isomer had substantially greater analgesic activity, indicates that factors other than enkephalinase inhibition may be important for R, S]-thiorphan's analgesic properties.