Benzisoxazole derivatives as Atypical Antipsychotic drugs: A Review

Antipsychotic medications constitute a diverse series of heterocyclic compounds that are used to treat psychotic problems, particularly schizophrenia and bipolar affective disorders. Heterocyclic molecules such as benzisoxazole derivatives, especially 3-(piperidin-4-yl)-1,2-benzisoxazole have been widely used as antipsychotic drugs. Atypical antipsychotic drugs which are derived from benzisoxazole include risperidone, iloperidone and paliperidone. Their therapeutic mechanism is to act as potent antagonists to D2 dopamine receptors and blocks 5-HT2A receptors. However, the administration of antipsychotic drugs is accompanied with propensity to cause extrapyramidal symptoms (EPS) such as psuedoparkinsonism, tardive dyskinesia, acute dystonic reactions and akathisia. Risperidone, paliperidone and iloperidone exhibit better efficacy compared to other known antipsychotic drugs, based on their mechanism in the dopaminergic and serotonergic systems. However other antipsychotic drugs have exhibited lesser propensity to cause EPS than the benzisoxazole derived drugs. Thus reconsideration of structure-function relationship of 3-(piperidin-4-yl)-1,2-benzisoxazole derived drugs and designing new molecules with changes in the structure that support lower propensity to cause EPS may serve a long drawn objective to design antipsychotic drugs with higher efficacy and lesser EPS. Risperidone, paliperidone and iloperidone categorized as atypical antipsychotic drugs [1] have principal action in humans, namely the repression of schizophrenia and bipolar affective disorders. The above drugs are classified as second generation atypical antipsychotics whose elementary mechanism of action is seen as D2/5HT2A antagonism with higher affinity towards 5HT2A [2]. Their ability to cause extrapyramidal side effects (EPS) in humans and catalepsy in mice has made them to be designated as neuroleptics [3]. They are known to block dopamine D2 receptors in the mesolimbic region, particularly stria terminalis, nucleus accumbens and the amygdale [4-6]. The drugs not only show affinity for D2/5HT2A but also for other cholinergic, histaminergic, 5-HT1A, α1-adrenoceptors systems thus designated as multi-acting receptor-targeted antipsychotics (MARTA) [7]. However the above mentioned atypical antipsychotics have been known to be more effective and safer than the conventional antipsychotics [8]. Earlier studies have exhibited comparable results in control of positive symptoms by both conventional and atypical antipsychotics and pre-eminence of atypical antipsychotics over conventional drugs in the control of negative symptoms and cognitive dysfunction [9]. Efficacy of atypical antipsychotics also include better functional capacity, increased quality of life, efficiency in patients with refractory problems and higher rate of response [10]. Nevertheless atypical antipsychotics exhibit characteristic side effects, their cognitive and metabolic side effects are of particular interest [11]. However, atypical antipsychotics according to earlier studies have been the first choice of medication in schizophrenia and bipolar disorders [12, 13], with iloperidone exhibiting better efficacy than other antipsychotics [14]. Interestingly few studies have revealed that atypical antipsychotics though considerably more efficacious than conventional antipsychotics but show equal propensity to cause extrapyramidal side effects [15]. However authors have found that benzisoxazole derivative antipsychotic drug risperidone were remarkably more efficacious than the conventional drugs, also showing better functional recovery. Risperidone were also found to be better than conventional antipsychotics with regard to positive symptoms and optimally higher with respect to negative symptoms and cognitive problems. The discussion reveal the heterogeneity in the function of benzisoxazole derived antipsychotics, however few studies also revealed superiority of these drugs as antipsychotics with same EPS rate as that of placebo [16, 17]. Mechanism of action of antipsychotics