title: Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes.
abstract: Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D(2) receptors, its anxiolytic properties from serotonin 5-HT(2C) receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT(2A) receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells (hD(2) and hD4.4 receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C) and h5-HT(7) receptors and hM(1), hM(2) and hM(3) receptors) and HEK-293 cells (h5-HT(3) receptors) or natively present in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors) and guinea pig cerebellum (H(1) central histamine receptors) membranes. Monodesmethyl cyamemazine showed a neurotransmitter receptor profile similar to that of its parent compound cyamemazine, i.e.: high affinity for h5-HT(2A) receptors (K(i)=1.5 nM), h5-HT(2C) receptors (K(i)=12 nM) and hD(2) receptors (K(i)=12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT(2A) receptors (K(i)=39 nM) and histamine H(1) receptors (K(i)=15 nM) and a reduced affinity for D(2) and 5-HT(2C) receptors. Therefore, monodesmethyl cyamemazine can contribute to enhance and prolong the therapeutic actions of cyamemazine. Further investigation is required to see if the high affinities of cyamemazine sulfoxide for H(1) and 5-HT(2A) receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.
authors.affiliation: Inserm U669, Hôpital Universitaire Paul-Brousse, Villejuif, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Benyamina
authors.forename: Christophe
authors.initials: C
authors.lastname: Arbus
authors.forename: Philippe
authors.initials: P
authors.lastname: Nuss
authors.forename: Ricardo P
authors.initials: RP
authors.lastname: Garay
authors.forename: Gervais
authors.initials: G
authors.lastname: Neliat
authors.forename: Ahcène
authors.initials: A
authors.lastname: Hameg
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008745:Methylation; D010640:Phenothiazines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism; D014162:Transfection
chemical_list: D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D008024:Ligands; D010640:Phenothiazines; D011954:Receptors, Dopamine; D011968:Receptors, Histamine; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D013454:Sulfoxides; C028457:cyamemazine