Ex vivo binding of flibanserin to serotonin 5-HT1A and 5-HT2A receptors.
Flibanserin has been reported to be an agonist at 5-HT1A-receptors and an antagonist at 5-HT2A receptors, with higher affinity for 5-HT1A receptors. Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects, flibanserin was shown to exert 5-HT2A antagonism at doses (4-5 mg kg-1) that are lower or equal to those required to stimulate 5-HT1A receptors. In order to understand this phenomenon, the interaction of flibanserin with 5-HT1A and 5-HT2A receptors was evaluated in ex vivo binding studies. This interaction was evaluated in the prefrontal cortex, hippocampus and midbrain by using [3H]8-OH-DPAT and [3H]ketanserin to label 5-HT1A and 5-HT2A receptors, respectively. Flibanserin was given at 1, 10 and 30 mg kg-1 intraperitoneally. The dose of 1 mg kg-1 displaced both radioligands preferentially in the frontal cortex. The doses of 10 and 30 mg kg-1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50% and 70%, respectively. The displacement was maximal after 0.5 h and was reduced or not evident after 3 h. We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects.
Boehringer Ingelheim Italia, Via Lorenzini 8, 20139 Milan, Italy
A
A
Scandroglio
E
E
Monferini
F
F
Borsini
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*
D001562:Benzimidazoles; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C098107:flibanserin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D007650:Ketanserin