The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.
Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, Bern, CH-3012, Switzerland. Electronic address: martin.lochner@dcb.unibe.ch.
Martin
M
Lochner
Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1PD, UK. Electronic address: ajt44@cam.ac.uk.
Andrew J
AJ
Thompson
D000818:Animals; D001285:Atropine / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D012601:Scopolamine / Q000378:metabolism* / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology; D014982:Xenopus laevis
D018727:Muscarinic Antagonists; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D001285:Atropine; D012601:Scopolamine
5-HT(3); Amygdala; Antagonist; Anxiety; Binding site; Cognition; Cys-loop; Depression; Hippocampus; Ligand docking; Memory; Muscarinic; Scopolamine