WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: A Novel Dopamine D₂ Receptor Partial Agonist/Serotonin Reuptake Inhibitor with Preclinical Antipsychotic-Like and Antidepressant-Like Activity

Abstract

The preclinical characterization of propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D 2 receptor (D 2L K i , 4.0 nM) and serotonin transporter (K i , 7.1 nM), potent D 2 partial agonist activity (EC 50 , 0.38 nM; E max , 30%), and complete block of the serotonin transporter (IC 50 , 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID 50 , 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D 2 partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D 2 receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic-and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.Schizophrenia is a debilitating disease that affects approximately 1% of the world population. The symptoms of schizophrenia can be loosely categorized into three main groups: positive symptoms, such as hallucinations and delusions; negative symptoms, such as social withdrawal and anhedo- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.157388.ABBREVIATIONS: SRI, serotonin reuptake inhibitor; 6-OHDA, 6-hydroxydopamine; propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one; WAY-100635, N-[2-[4-(2-methoxyphenyl)

Dopamine Receptor Homooligomers and Heterooligomers in Schizophrenia

“…Nonetheless, the therapeutic benefits of these drugs appear promising, indicating that these types of antipsychotics may warrant additional attention. For example, preclinical studies have shown that the putative antipsychotic WS500‐30, a partial D2 receptor agonist and serotonin transporter blocker, may have potential for the therapeutic management of both psychosis and cognitive defects in schizophrenia [56]. Similarly, the mGlu2/3 receptor glutamate agonist LY404039, also with partial activity at the D2 receptor [57–59], is efficacious in alleviating both the positive and negative symptoms [60].…”

Development and application of an LC–MS/MS method for measuring the effect of (partial) agonists on cAMP accumulation in vitro

“…Brennan et al, 2010) and in other cell systems. For example, we have validated cAMP accumulation in CHO cells transfected with the serotonergic 5-HT 1A and cannabinoid CB 1 and CB 2 receptors (e.g.…”

Aripiprazole in the treatment of Alzheimer's disease

“…Aripiprazole (0.1 --1 mg/kg i.p.) caused a dose-dependent antagonism of psychostimulant-induced stereotypies (sniffing--licking--gnawing syndrome) and climbing behavior in CF-1 mice [88]. Aripiprazole has also been shown to dosedependently reverse psychostimulant-induced disruption of PPI in rats (1, 3, 10 and 30 mg/kg p.o.)…”

“…Much preclinical work has focused on the presumed reduced side effects of aripiprazole versus second-generation antipsychotics [81][82][83][84][85][86][87][88][89][90]. Though aripiprazole has not been evaluated in established animal models for AD, several preclinical studies underpin the presumed efficacy of aripiprazole with regard to NPS-related behavioral changes, as well as cognitive deficits in laboratory animals.…”

“…or 10 mg/kg p.o. [88]) and ICR mice (3 --20 mg/kg s.c.) [84]. However, aripiprazole (10 mg/kg, i.p.)…”