Burimamide, a histamine (HA) derivative with both H
2- and H
3-blocking
properties, induces antinociception when injected into the rodent
CNS. Several related compounds share this property, and structure-activity
studies have shown that this new class of analgesics is distinct
from known HA antagonists. The prototype, named improgan, shows
a preclinical profile of a highly effective analgesic, with
activity against thermal, mechanical and inflammatory nociception
after doses that do not alter motor balance or locomotor activity.
Improgan analgesia is not blocked by opioid antagonists and
is observed in opioid receptor knock-out mice. Unlike morphine,
improgan does not induce tolerance after daily dosing. Extensive
in vitro pharmacology studies have excluded known histaminergic,
opioid, serotonergic, GABAergic and adrenergic receptor mechanisms,
as well as 50 other sites of action. The improgan-like analgesic
activity of some HA congeners suggests an analgesic action on
a novel HA receptor, but further studies are required to substantiate
this. Studies in progress are characterizing the sites and mechanisms
of action of improgan, and developing brain-penetrating derivatives
that could be useful for clinical pain.
