Lu AE58054 is an in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist with a Ki value of 0.83 nM.
IC50 Value: 0.83 nm
Target: 5-HT(6)R
in vitro: Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined.
in vivo: Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157, with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia.
Clinical trial: Lu-AE58054 Added to Donepezil for the Treatment for Moderate Alzheimer's Disease. Phage2

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