Affinities for 5HT2A D2 Receptors and 5HT2C Receptors

Interest in the role of 5-HT in schizophrenia was revived by the hypothesis that clozapine and other antipsychotics with minimal potential to impair motor function (so-called atypical antipsychotic drug) were more potent 5-HT2A than DA D2 antagonists (Meltzer 1989). This hypothesis, now generally accepted, led to the development of a group of antipsychotic drugs that are among the most widely used of the antipsychotic drugs. The drugs currently approved or close to approval are listed in Table 14.1, along with their affinities for human 5-HT2A, D2, and 5-HT2C receptors, as well as their 5-HT2A/ D2, 5-HT2C / D2, and 5-HT2A/2C ratios. These data are obtained fromthe National Institute ofMental Health (NIMH) Psychopharmacology Drug Screening Program Website. For most drugs, the ligand used to determine the 5-HT2C affinity was [3H]mesulergine; for 5-HT2A receptors, [3H]ketanserin; and for DA, [3H]spiperone. Where available, the tissue source was human cortex; for some, it was cloned receptors expressed in cell lines. It should be noted that aripiprazole is a partial agonist at the D2 receptor and achieves much weaker blockade of the 5-HT2A receptor than would be expected based on its Ki value. It is evident that the atypical antipsychotic drugs, with the exception of aripiprazole, have higher affinities for 5-HT2A than D2 receptors have. Only 6 of 12 atypicals have a higher affinity for the 5-HT2C than the D2 receptor has. Iloperidone, lurasidone, melperone, risperidone, sertindole, and aripiprazole do not. All atypicals with the exception of asenap-ine have a higher affinity for the 5-HT2A than 5-HT2C receptor has. None of the typical antipsychotic drugs has a higher affinity for the 5-HT2C than the D2 receptor has. Thus, from this perspective, it is unlikely that there is a systematic effect of the 5-HT2C receptor for the action of all antipsychotic drugs as there appears to be for the D2 receptor or for all atypical antipsychotic drugs, as there appears to be for the 5-HT2A receptor. Nevertheless, it is quite possible that for some atypical antipsy-chotic drugs, at clinically relevant doses, the 5-HT2C receptor is important for some actions. This will be discussed subsequently.

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