The selective
kappa-opioid receptor agonist
spiradoline mesylate (
U62,066E), an arylacetamide, was synthesized with the intention of creating an
analgesic that, while still retaining its
analgesic properties, would be devoid of the, mainly
mu receptor mediated, side effects such as physical dependence and
respiratory depression associated with
morphine.
Spiradoline is highly selective for the
kappa receptor with K(i) of 8.6 nM in guinea pig. Examination of the enantiomers of
spiradoline, showed the (-)enantiomer to be responsible for the kappa agonist properties.
Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies,
spiradoline has a short duration of action with a peak at around 30 min after administration. The
analgesic properties of
spiradoline are well documented in mice and rats.
Antitussive properties have also been reported in rats. Furthermore,
spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of
ischemia. In humans,
spiradoline is a potent
diuretic. It also produces significant sedation presumably due to its
antihistamine properties. Preclinical studies have shown that
spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings.
kappa Receptors inhibit dopaminergic neurotransmission.
Spiradoline, given systematically to rats, produces a significant and long lasting decrease in
dopamine release, and in locomotor activity. It has also
antipsychotic-like effect in animal behavioral tests. At low doses
spiradoline was reported to decrease
tics in patients with
Tourette's syndrome. Although
spiradoline had promising effects in animal tests of
analgesia, and a reasonably good safety profile in preliminary studies, it did not replace
morphine as an
analgesic. The available clinical data suggest that
spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for
analgesic effects. Thus, future development of
spiradoline-like
analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system.
Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a
neuroprotective agent.