The chemical development of selective and specific serotonin S₂‐antagonists

Abstract

Four types of chemical intermediates were prepared to synthesize novel piperidine derivatives inspired by the butyrophenones benperidol and lenperone and by the diphenylbutyl neuroleptic pimozide. The first type, comprising benzimidazolone alkyl intermediates, yielded declenperone and milenperone and also the "symmetrical" compound domperidone, which was pharmacologically unusual by its specific peripheral dopamine antagonism. Declenperone was the most potent serotonin antagonist of that series, and replacement of the benzimidazolinonepropyl by the quinazolinedioneethyl moiety led to ketanserin, which was devoid of residual dopamine antagonism. Very potent serotonin S2-antagonists were also obtained by using intermediates prepared from 2-aminoaza-heterocycles. Pirenperone and setoperone had a complex pharmacological profile, including significant dopamine and norepinephrine antagonism. These activity components were absent from the profile of R 56413 and ritanserin, which were obtained by using the fourth intermediate, benzhydrylenepiperidine. R 56413 and ritanserin are the most specific of the presently known serotonin S2-antagonists.

Effects of seganserin, a 5-HT2 antagonist, and temazepam on human sleepsstages and EEG power spectra

“…Seganserin (R56413, Janssen Pharmaceutica, N.V.) is a highly specific 5HT 2 antagonist devoid of dopaminergic activity (Kennis et al, 1986). The plasma half-life is 26.1 _+ 12.9 (S.D.)…”

Synthesis and In‐vivo Evaluation of Carbonyl‐amide Linkage Based New Benzimidazole Derivatives

“…Some of the important benzimidazole derivatives have been reported as proton pump inhibitor [24], anti-dopaminergic Domperidone [25], anti-psychotic Pimozide [26], thyroid receptor agonists [27], gonadotropin releasing hormone receptor antagonists [28] and interestingly alkynylbenzimidazoles as modulators of metabotropic glutamate receptors [29]. Recently, we have also published some series of biologically active benzimidazole derivatives [30,31].…”

Lipophilicity Study of Thiazolo[3,2-a]pyrimidine Derivatives as Potential Bioactive Agents

“…[1][2][3][4] Setoperone is an antagonist with high affinity and specificity for serotonine 5HT 2 receptors. Moreover setoperone also binds to dopamine D 2 receptors and it is effective as treatment of patients with chronic schizophrenia.…”

“…Moreover setoperone also binds to dopamine D 2 receptors and it is effective as treatment of patients with chronic schizophrenia. 1,[5][6][7][8] Other thiazolo[3,2-a]pyrimidine derivatives display antibacterial, 9 antiviral, 8,10 and analgesic 11 activities as well as hypotensive. 6 Lipophilicity is an important parameter to expect biological activity of the compounds.…”