Stable
amides of
clozapine derived from
fatty acids prominent in cerebral tissue might enhance the central activity of
clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique
drug, which is the only agent with securely established superior
antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity.
Amide derivatives of
clozapine were prepared from structurally varied
fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by
dopamine agonist apomorphine and to induce
catalepsy. Their duration-of-action and potency were compared to free
clozapine, and concentrations of
clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at
dopamine receptors and other potential
drug-target sites.
Clozapine-N-
amides of linoleic, myristic, oleic, and
palmitic acids had moderate initial central depressant activity but by 6 h, failed to inhibit arousal induced by
apomorphine. However, the
docosahexaenoic acid (DHA) derivative was orally bioavailable, 10-times more potent (ED(50) 5.0 micromol/kg) than
clozapine itself, and very long-acting (>/= 24 h) against
apomorphine, and did not induce
catalepsy. DHA itself was inactive behaviorally.
Clozapine showed expected
dopamine receptor affinities, but DHA-
clozapine was inactive at these and other potential target sites. After systemic administration of DHA-
clozapine, serum levels of free
clozapine were very low, and brain concentrations somewhat lower than after administering
clozapine. DHA-
clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after
oral administration or injection without inducing
catalepsy, and it markedly reduced peripheral exposure to free
clozapine. It lacked the receptor-affinities shown by
clozapine, suggesting that DHA-
clozapine may be a precursor of free, pharmacologically active
clozapine. Such agents may represent potential
antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety.