The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist
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l-Stepholidine, a dopamine D2 antagonist with D1 agonist activity, should in theory control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. Though several articles describe its impact on the dopamine system, it has not been systematically evaluated and compared to available antipsychotics.
Materials and methods
We examined its in vitro interaction with dopamine D2 and D1 receptors and compared its in vivo pharmacokinetic profile to haloperidol (typical) and clozapine (atypical) in animal models predictive of antipsychotic activity.
In vitro, l-stepholidine showed significant activity on dopamine receptors, and in vivo, l-stepholidine demonstrated a dose-dependent striatal receptor occupancy (RO) at D1 and D2 receptors (D1 9–77%, 0.3–30 mg/kg; D2 44–94%, 1–30 mg/kg), though it showed a rather rapid decline of D2 occupancy related to its quick elimination. In tests of antipsychotic efficacy, it was effective in reducing amphetamine- and phencyclidine-induced locomotion as well as conditioned avoidance response, whereas catalepsy and prolactin elevation, the main side effects, appeared only at high D2RO (>80%). This preferential therapeutic profile was supported by a preferential immediate early gene (Fos) induction in the nucleus accumbens over dorsolateral striatum. We confirmed its D1 agonism in vitro, and then using D2 receptor, knockout mice showed that l-stepholidine shows D1 agonism in the therapeutic dose range.
Thus, l-stepholidine shows efficacy like an “atypical” antipsychotic in traditional animal models predictive of antipsychotic activity and shows in vitro and in vivo D1 agonism, and, if its rapid elimination does not limit its actions, it could provide a unique therapeutic approach to schizophrenia.
Keywordsl-Stepholidine Antipsychotic D1 and D2 receptor occupancy Schizophrenia Animal models
This study was funded by a Stanley Medical Research Institute grant (#04R-826) to Shitij Kapur. Susan R. George was supported by a grant from the National Institute on Drug Abuse. The authors would like to thank Jun Parkes of the PET group, Roger Raymond of the Neuroimaging Section of CAMH, and George Varghese from the Department of Pharmacology, University of Toronto for their technical assistance.
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