Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats

Abstract

The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. 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. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), 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. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

“…The 5-HT6 serotonin receptor (5-HT6R) is a promising target to treat a variety of neurological and cognitive disorders, including cognitive impairment, Parkinson's, Alzheimer's, obesity, schizophrenia, motor disorders, sleep, and depression (Mitchell and Neumaier, 2005;Hirst et al, 2006;Wesolowska and Nikiforuk, 2007;Ferguson et al, 2008;King et al, 2008;Morairty et al, 2008;Arnt et al, 2010;Carr et al, 2010;Meffre et al, 2012;M W J de Bruin and G Kruse, 2015;Aldrin-Kirk et al, 2016;Brodsky et al, 2016). Despite mounting evidence for the therapeutic value of this receptor, little is known about the specific mechanisms underlying 5-HT6R signaling.…”

Alzheimer’s Disease: Dawn of a New Era?

“…Antagonists of 5-HT6 are under development for AD. Idalopirdine (Lu AE58054) is a 5-HT6 that has been reported to be highly selective, aside from some affinity for adrenergic receptors (140). Lu AE58054 has successfully undergone phase I trials in healthy volunteers.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…These deficits were also reversed by D 1 R agonism, the effect of which was facilitated by 5-HT 1A and mGlu 2/3 receptor signaling (Horiguchi et al, 2013). Recently, Lu AE58054 (2-(6-fluoro-1H-indol-3-yl)-N-[[3-(2,2,3,3-tetrafluoropropoxy) phenyl]methyl]ethanamine), a 5-HT 6 receptor antagonist, was found to reverse subchronic PCP-induced deficits in novel object recognition test (Arnt et al, 2010). It is not known whether any of the drug treatments can produce persistent reversal of subchronic PCP effects, but, interestingly, clozapine and haloperidol prevented the metabolic hypofunction and the reduced Pv expression in several brain regions in rats treated intermittently with PCP (Cochran et al, 2003).…”