We designed
phethiol (1-amino-1-benzyl-2-mercaptoethane) as a potent and selective inhibitor of Zn-containing
aminopeptidases. This compound inhibited purified
aminopeptidase M (EC.3.4.11.2) with a Ki of 5 nM but was at least 1000 times less potent against other
metallopeptidases comprising
angiotensin-converting enzyme EC 3.4.15.1),
enkephalinase (EC 3.4.24.11),
thermolysin (EC 3.4.24.4), or dipeptidylaminopeptidases.
Phethiol alone significantly but partially protected endogenous (Met5)
enkephalin released from depolarized brain slices, total protection being achieved when it was associated with an
enkephalinase inhibitor. In order to obtain a parenterally-active inhibitor of cerebral
aminopeptidases, the
prodrug carbaphetiol, a readily hydrolyzable S-phenylcarbamoyl derivative of
phethiol, was designed.
Carbaphethiol (i.v.) elicited a rapid rise in mouse striatal level of
Tyr-Gly-Gly, a characteristic extracellular metabolite of
enkephalins. Carbapethiol alone and, even more, when associated with an
enkephalinase inhibitor, exerted a potent
naloxone-reversible antinociceptive activity.
Carbaphethiol appears as the first parenterally-active inhibitor of cerebral
aminopeptidases, potentially useful in
neuropeptides degradation studies and as a
pain-suppressing agent.