Antipsychotics 5-HT2A receptor antagonist

In experimental studies, many clinically effective neuroleptics have been shown to act as 5-HT2A receptor antagonists. Studies on post-mortem brain from schizophrenic patients have shown that the decrease in the number of 5-HT2A receptors in the prefrontal cortex might be related to the disease process. It therefore seems unlikely that the antipsychotic activity of neuroleptics can be explained solely in terms of their action on 5-HT receptors. Furthermore, no correlation exists between the average therapeutic doses of a neuroleptic and its affinity for 5-HT receptors. It does seem possible, however, that several atypical neuroleptics such as amperozide, risperidone and possibly ritanserin do owe at least part of the pharmacological profile to their ability to inhibit 5-HT receptors. 

Iloperidone is a novel antipsychotic drug which is a mixed dopamine D2/serotonin 5-HT2A receptor antagonist. In 2008, the US Food and Drug Administration required Vanda Pharmaceuticals, the manufacturers, to carry out a comparison of iloperidone with placebo and an active comparator such as olanzapine or risperidone [80 ]. It was finally approved in the USA in May 2009. 

Aripiprazole is the most recently approved atypical antipsychotic. This medication has a high affinity for D2 and D3 receptors, as well as 5-HTand 5-HT2a receptors. Although the mechanism of action is not known, aripiprazole may mediate its effects via a combination of partial agonist activity at the D2 and 5-HTj receptors and antagonist activity at the 5-HT2 receptor. 

Of the clinically tested new antipsychotics, ziprasidone has the highest 5-HT2A/D2 receptor-affinity ratio. Ziprasidone is an antagonist at the a -adrenoreceptor, but its affinity is half that of its D 2 affinity. In addition, compared with its affinity for D 2 and 5-HT2A receptors, ziprasidone has a relatively low affinity for histamine receptors (pKJ = 7.33). In vitro, ziprasidone is a moderately potent inhibitor of neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. This property is shared with some antidepressants, and contrasts with risperidone, which is inactive at all three monoamine uptake sites. 

Most antipsychotics,but also many non-an-tipsychotic drugs, reverse deficits in PPI induced by amphetamine or apomorphine (152, 153). In contrast, Dg receptor antagonists such as haloperidol fail to reverse deficits in PPI induced by PCP or dizocilpine (153-156), while such deficits are, at least in part, reversed by clozapine (156), remoxipride (157), olanzapine (158), and quetiapine (155). Risperidone fails to reverse the effect of PCP (155), but it antagonizes the disruption of PPI induced by the 5-HT2A agonist DOI (150,153). 

Clozapine (Clozaril), a 5-HT2A/2c-receptor antagonist, represents a class of atypical antipsychotic drugs with reduced incidence of extrapyramidal side effects compared to the classical neuroleptics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia. Clozapine also has a high affinity for subtypes of dopamine receptors. 

The thienobenzodiazepine olanzapine is an effective atypical antipsychotic agent that is close in structure to clozapine but has a somewhat different neuropharmacological profile, in that it is a more potent antagonist at dopamine D2 and, especially, serotonin 5-HT2A receptors (15). Olanzapine is well absorbed after oral administration and is metabolized mainly by CYP1A2 to inactive metabolites, with a variable half-life of approximately 20 to 50 hours. 

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