5-HT2A receptor antagonist antidepressants

Marek, G. J., Martin-Ruiz, R., Abo, A. Artigas, F. (2005). The selective 5-HT2A receptor antagonist Ml00907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology, 30, 2205-2215. 

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. 

Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone s benefits as an antidepressant might be attributed to this effect. Trazodone also has weak-to-moderate presynaptic -adrenergic blocking properties and is a modest antagonist of the Hi receptor. 

Mirtazapine is a tetracyclic antidepressant, similar to mianserin, and is a potent 5-HT2a/2c receptor antagonist. It has been successfully used to treat akathisia. In a doubleblind, placebo-controlled study in 26 patients with schizophrenia who were receiving neuroleptic drugs, mirtazapine 15 mg/day for 5 days was associated with less akathisia (227). 

The first second-generation antidepressant an alpha-2 adrenoceptor antagonist with some affinity for S-HT a/ 5-HT2a arid 5-HT3, alpha-1 adrenoceptors and HI receptors... 

Various tricyclic antidepressants and SSRIs, including fluoxetine, also bind at 5-HT2A and 5-HT2C receptors (141,142). The role, if any, that is derived from a direct interaction of these agents with 5-HT2 receptors versus their interaction at the 5-HT transporter remains to be elucidated. In general, 5-HT2 antagonists downregulate... 

Ritanserin (Fig. 18.47) acts as a potent but non-selecdve 5-HT2A/2B/2C antagonist with moderate affinities for dopamine receptors and appears to produce some reduction of schizophrenic core symptoms. It may also show antidepressant and anxiolytic properties. The antipsychotic effects could be improved by increasing the D2/5HT2 affinity ratio by structural modification, resulting in risperidone (Fig. 18.47). 

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