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.
Scott
W L
WL
Mendelsohn
L G
LG
Cohen
M L
ML
Evans
D A
DA
Frederickson
R C
RC
D000603:Amino Acids, Sulfur / Q000494:pharmacology*; D000700:Analgesics; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D015260:Neprilysin; D011480:Protease Inhibitors; D013237:Stereoisomerism; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D000603:Amino Acids, Sulfur; D000700:Analgesics; D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D015244:Thiorphan; D008625:Tiopronin; D015260:Neprilysin