Radioligand binding and photoaffinity labelling studies show a direct interaction of phenothiazines at 5-HT3 receptors.
The effects of a range of phenothiazines were examined on 5-hydroxytryptamine3 (5-HT3) receptors in membranes from NIE-115 neuroblastoma cells using radioligand binding. Chlorpromazine, fluphenazine, perphenazine, trifluoperazine and prochlorperazine inhibited specific binding of both the 5-HT3 receptor antagonist [3H]GR65630 and agonist [3H]meta-chlorophenylbiguanide (mCPBG), with Ki values ranging from 0.4 to 3.9 microM. The mode of action of chlorpromazine was further examined using photoaffinity labelling in the presence and absence of 5-HT. Saturation radioligand binding data with both [3H]GR65630 and [3H]mCPBG showed that photoaffinity labelling with chlorpromazine (1 microM) caused a decrease in the maximum number of binding sites observed (35% and 28% for agonist and antagonist, respectively). This decrease was not observed when the membranes were incubated in the presence of 5-HT. The results demonstrate a direct interaction of a range of phenothiazines at the 5-HT3 receptor binding site.
Lummis
S C
SC
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, U.K.
Baker
J
J
D000345:Affinity Labels; D000818:Animals; D001645:Biguanides / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D010640:Phenothiazines / Q000494:pharmacology*; D010777:Photochemistry; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000345:Affinity Labels; D001645:Biguanides; D007093:Imidazoles; D007211:Indoles; D010640:Phenothiazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C059068:GR 65630; C065734:1-(3-chlorophenyl)biguanide