Fatty acid derivatives of clozapine: Prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat

Stable amides of clozapine derived from fatty acids prominent in cerebral t issue might enhance the central activity of clozapine and reduce its exposu re to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior an tipsychotic effectiveness, but with a risk of potentially lethal systemic t oxicity. Amide derivatives of clozapine were prepared from structurally var ied fatty acid chlorides and evaluated for ability to inhibit behavioral ar ousal in rat induced by dopamine agonist apomorphine and to induce cataleps y. Their duration-of-action and potency were compared to free clozapine, an d concentrations of clozapine were assayed in brain and blood. Selected age nts were also evaluated for affinity at dopamine receptors and other potent ial 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 docosahexae noic acid (DHA) derivative was ovally bioavailable, 10-times more potent (E D50 5.0 mu mol/kg) than clozapine itself and very long-acting (greater than or equal to 24 h) against apomorphine, and did not induce catalepsy. DHA i tself was inactive behaviorally. Clozapine showed expected dopamine recepto r affinities, but DHA-clozapine was inactive at these and other potential t arget sites. After systemic administration of DHA-clozapine, serum levels o f free clozapine were very low, and brain concentrations somewhat lower tha n after administering clozapine. DHA-clozapine is a long-acting central dep ressant with powerful and prolonged antidopaminergic activity after oral ad ministration or injection without inducing catalepsy, and it markedly reduc ed peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of fr ee, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and pos sibly enhanced safety. (C) 2000 American College of Neuropsychopharmacology . Published by Elsevier Science Inc.