Serotonin 5-HT2A receptor antagonist

A serotonin 5-HT_2A receptor antagonist, or simply 5-HT_2A antagonist, is a drug which acts as an antagonist of the serotonin 5-HT_2A receptor.^[1] Aside from simple competitive antagonists, these drugs may also be inverse agonists of the serotonin 5-HT_2A receptor.^[2][3][4][5]

They include non-selective agents like atypical antipsychotics, tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), and serotonin antagonists and reuptake inhibitors (SARIs) as well as selective agents.^[1][6][7] Examples of non-selective serotonin 5-HT_2A receptor antagonists include antipsychotics like chlorpromazine, clozapine, olanzapine, quetiapine, risperidone, spiperone (spiroperidol), and ziprasidone; antihistamines like cyproheptadine, hydroxyzine, and LY-2624803; TCAs like amitriptyline, clomipramine, doxepin, imipramine, iprindole, and trimipramine; TeCAs like mianserin, mirtazapine, and esmirtazapine; SARIs and related like trazodone, nefazodone, mepiprazole, niaprazine, and lubazodone; and others like adatanserin, cyclobenzaprine, deramciclane, DSP-6745, flibanserin, landipirdine, metergoline, metitepine (methiothepin), MT-1207, opiranserin, pizotifen, roluperidone, and XOB (ASR-6001).^[1][6][7] More selective serotonin 5-HT_2A receptor antagonists include 4-PhPr-PEA, 4F-4PP, AMDA, altanserin, butanserin, cinanserin, eplivanserin, fananserin, glemanserin, iferanserin, ketanserin, lidanserin, LY03017, metrenperone, NH130, pelanserin, pimavanserin, pirenperone, pruvanserin, R-96544, R-102444, remlifanserin, ritanserin, seganserin, setoperone, SpAMDA, and volinanserin.^[1][6][7] Peripherally selective or acting serotonin 5-HT_2A receptor antagonists are known as well and include BW-501C67, irindalone, naftidrofuryl, sarpogrelate, temanogrel, trelanserin, and xylamidine.^[8]

Selective serotonin 5-HT_2A receptor antagonists have been studied in the treatment of sleeping disorders such as insomnia, psychiatric disorders such as depression, anxiety, and schizophrenia, and for other indications.^[7][9][10] Several selective serotonin 5-HT_2A receptor antagonists reached and/or completed phase 3 clinical trials, including and eplivanserin, pimavanserin, pruvanserin, and volinanserin.^{[9][10][11][12]} However, all of them except pimavanserin were discontinued, with pimavanserin having been approved only for the treatment of Parkinson's disease psychosis.^[9][13][14] Though not approved for insomnia, selective serotonin 5-HT_2A receptor antagonists have been found to improve sleep and sleep quality, including increasing deep slow wave sleep (SWS) without affecting REM sleep.^{[7][12][6][9][15][16]}

Serotonin 5-HT_2A receptor antagonists are useful as so-called "trip killers" or hallucinogen antidotes in aborting or shortening the effects of serotonergic psychedelics like psilocybin, LSD, and mescaline.^{[17][18][19][20]} Ketanserin, risperidone, chlorpromazine, and cyproheptadine have all been formally studied and found to be effective for such purposes.^[17][18] Ketanserin, pimavanserin, and eplivanserin/volinanserin are under formal development and/or study for this use as well.^{[21][22][23][24][25][26][27][28]} In addition, recreational psychedelic users often use trip killers to abort psychedelic experiences, with frequent use of trazodone, quetiapine, olanzapine, and mirtazapine for these purposes having been documented.^[29][30]