A 5-HT6 receptor antagonist
Lu AE58054 hydrochloride is an in-vivo binding affinity and effect, in-vitro selectivity and potency of 5-HT(6)R antagonist with Ki value of 0.83 nM [1].
The serotonin6 receptor (5-HT6R) is one of 14 known 5-HTRs in the serotonin receptor family [1]. It plays an important role in cognitive impairments associated with Alzheimer's disease and schizophrenia [2].
In the 5-HT(6) GTP gamma S efficacy assay, Lu AE58054 showed potent inhibition of 5-HT-mediated activation. Apart from medium affinity to adrenergic alpha (1B)- and alpha(1A)-adrenoreceptors, Lu AE58054 shows >50-fold selectivity compared with more than 70 targets examined [1].
In rats model, Orally administered Lu AE58054 inhibited binding of the 5-HT6 antagonist Lu AE60157 with ED50 of 2.7 mg/kg. Administration of Lu AE58054 in a dose range (5–20 mg/kg) leading to above 65% 5-HT6R binding, which reversed cognitive impairment in rats treatment with phencyclidine. These results indicate that Lu AE58054 is a potent antagonist of 5-HT6Rs with good oral bioavailability in the rat model of cognitive impairment in schizophrenia [1].
参考文献:
[1]. Arnt J, Bang-Andersen B, Grayson B, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol, 2010, 13(8): 1021-1033.
[2]. Witten L, Bang-Andersen B, Nielsen SM, et al. Molecular and Cellular Pharmacology
Characterization of [3H]Lu AE60157 ([3H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine6 (5-HT6) receptors in vivo. Eur J Pharmacol, 2012, 676(1-3): 6-11.
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