Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes

Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D2 receptors, its anxiolytic properties from serotonin 5-HT2C receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT2A 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 (hD2 and hD4.4 receptors, h5-HT1A, h5-HT2A, h5-HT2C and h5-HT7 receptors and hM1, hM2 and hM3 receptors) and HEK-293 cells (h5-HT3 receptors) or natively present in rat cerebral cortex (non-specific α1- and α2-adrenoceptors, GABAA and GABAB receptors) and guinea pig cerebellum (H1 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-HT2A receptors (Ki = 1.5 nM), h5-HT2C receptors (Ki = 12 nM) and hD2 receptors (Ki = 12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT2A receptors (Ki = 39 nM) and histamine H1 receptors (Ki = 15 nM) and a reduced affinity for D2 and 5-HT2C 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 H1 and 5-HT2A receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.