All marketed antipsychotics act by blocking dopamine D2 receptors. Fast dissociation from D2 receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D2 receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified JNJ 37822681 as a fast-dissociating D2 ligand. Its D2 receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects (α1, α2, H1, Muscarinic, 5-HT2C), nor affinity for receptors that may interfere with the effects of D2 antagonism (D1, D3, 5-HT2A). JNJ-37822681 occupied D2 receptors in rat brain at relatively low dose (ED50=0.39 mg/kg) and was effective in animal models of psychosis (eg, inhibition of apomorphine-induced stereotypy or d-amphetamine/ phencyclidine-induced hyperlocomotion). Increased prolactin levels were measured from an ED50 (0.169 mg/kg, peripheral D2 receptors) close to the ED50 required for apomorphine antagonism (0.194 mg/kg, central D2 receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ 37822681 induced catalepsy and inhibited avoidance behavior, but with a dissociation relative to antagonism of apomorphine-induced stereotypy that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger dissociation (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression for JNJ 37822681. JNJ 37822681 is a novel, potent, specific, centrally-active, fast-dissociating D2 antagonist with optimal brain disposition and the first compound that allows evaluation of the potential value of fast D2 antagonism for the treatment of schizophrenia and bipolar disorder.
- Received December 20, 2011.
- Revision received April 4, 2012.
- Accepted April 4, 2012.
- The American Society for Pharmacology and Experimental Therapeutics