Atypical antipsychotic profile of NRA0045, a novel dopamine D4 receptor, 5-hydroxytryptamine2(A) (5-HT2(A)) receptor and α1 adrenoceptor antagonist

Abstract

NRA0045 has high in vitro affinities for the dopamine D4 receptor, 5-HT(2A) receptor, and α1 adrenoceptor (38). NRA0045 occupies the frontal cortical 5-HT(2A) receptor and the α1 adrenoceptor without occupying the dopamine D2 receptor in the striatum and nucleus accumbens in vivo, and in vivo receptor occupancy of NRA0045 was similar to that of other atypical antipsychotics such as clozapine and risperidone (9). Thus, in vitro receptor binding and in vivo receptor occupancy clearly show that NRA0045 has an atypical antipsychotic nature. Moreover, NRA0045 inhibited quinpirole-stimulated [35S]GTPγS binding to the D4 receptor (67), and antagonized both tryptamine-induced seizures and NE-induced lethality (38). Therefore, NRA0045 is a dopamine D4 receptor, 5-HT(2A) receptor, and α1 adrenoceptor antagonist. NRA0045 showed activity in numerous models used to predict efficacy against the symptoms of schizophrenia. NRA0045 potently attenuates MAP-induced hyperactivity (37,38), while it has no effect on MAP-induced stereotyped behavior and does not induce catalepsy (37,38). MAP-induced hyperactivity is considered to be related to the activation of the mesolimbic dopaminergic system (16), while MAP-induced stereotyped behavior is attributed to activation of the nigrostriatal dopaminergic system (16,21). Activation of the mesolimbic dopaminergic system is likely to be involved in the pathophysiology of schizophrenia, while the activation of nigrostriatal dopaminergic system leads to EPS (16,21). Therefore, NRA0045 may have antipsychotic potential without EPS. NRA0045 shows atypical antipsychotic activities in different in vivo studies. NRA0045 improved apomorphine-induced disruption of PPI and PCP-induced prolonged swimming latency in a water maze task (37). These models are used to predict the therapeutic properties of atypical antipsychotics and the effect of NRA0045 was similar to that seen with clozapine but not haloperidol (37). Moreover, NRA0045 reversed the inhibitory effect of MAP on A10 dopamine neurons more potently than on A9 dopamine neurons and induced Fos protein in the medial prefrontal cortex and nucleus accumbens (36,37). Similar observations were seen with clozapine, but not haloperidol. Although conventional antipsychotics alleviate the positive symptoms in schizophrenia, they do not improve the negative symptoms and they induce EPS. In contrast, greater improvements in negative symptoms are seen in patients on clozapine, which is associated with fewer EPS (4,64). Moreover, in contrast to conventional antipsychotics, clozapine improves cognitive function, especially attention, verbal fluency, and retrieval from reference memory in patients with schizophrenia (4,64). The involvement of the dopamine D4 receptor in schizophrenia is controversial. It was reported that L-745,870, a selective dopamine D4 receptor antagonist, was ineffective in humans (28). It was also reported that the relatively lower doses of L-745,870 failed to reverse the disruption of PPI by apomorphine, while higher doses reversed it (6,31). Therefore, the doses used in a clinical trial were likely inadequate. Moreover, a selective dopamine D4 receptor antagonist, U-101387, increased c-fos expression in the medial prefrontal cortex as did clozapine and NRA0045, although the 5-HT2 receptor antagonist ritanserin failed to mimic clozapine-induced increase in Fos protein in the nucleus accumbens and medial prefrontal cortex. Therefore, dopamine D4 receptor blockade may be involved, at least in part, in the pharmacological actions of NRA0045. NRA0045 is a potent dopamine D4 receptor, 5-HT(2A) receptor and α1 adrenoceptor antagonist, and pharmacological profiles show that NRA0045 may have unique antipsychotic activity without the EPS seen with conventional antipsychotics. Whether data from studies conducted in rodents can be extrapolated to humans remains to be determined.