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.
Subject(s)
Anti-Anxiety Agents/metabolism , Antipsychotic Agents/metabolism , Phenothiazines/metabolism , Receptors, Dopamine/metabolism , Receptors, Histamine/metabolism , Receptors, Serotonin/metabolism , Animals , Anti-Anxiety Agents/pharmacology , Antipsychotic Agents/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Guinea Pigs , Humans , Ligands , Methylation , Phenothiazines/pharmacology , Protein Binding , Radioligand Assay , Rats , Receptors, Dopamine/drug effects , Receptors, Dopamine/genetics , Receptors, Histamine/drug effects , Receptors, Histamine/genetics , Receptors, Serotonin/drug effects , Receptors, Serotonin/genetics , Recombinant Proteins/metabolism , Sulfoxides/metabolism , TransfectionABSTRACT
The potency of three sulphonylureas, glibenclamide, glimepiride and gliclazide in antagonizing the vasorelaxant action of openers of adenosine triphosphate (ATP)-regulated K+ channel (KATP) was studied in vivo and in vitro in micro- and macrovessels, respectively. In the hamster cheek pouch, the vasodilatation and the increase in vascular diameter and blood flow induced by diazoxide were markedly reduced by the addition of either glibenclamide or glimepiride (0.8 microm) while they were not affected by gliclazide up to 12 microm. Similarly, in rat and guinea-pig isolated aortic rings, glibenclamide, glimepiride and gliclazide reduced the vasodilator activity of cromakalim. However, the inhibitory effect of gliclazide was considerably less when compared with either glimepiride or glibenclamide. These results suggest that, in contrast to glibenclamide and glimepiride, therapeutically relevant concentrations of gliclazide do not block the vascular effects produced by KATP channel openers in various in vitro and in vivo animal models.
