title: 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.
authors.affiliation: Lundbeck Research Denmark, H. Lundbeck A/S, Valby, Denmark. JA@lundbeck.com
authors.forename: Jorn
authors.initials: J
authors.lastname: Arnt
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Ben
authors.initials: B
authors.lastname: Grayson
authors.forename: Franklin P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cohen
authors.forename: Neil W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: Bruno
authors.initials: B
authors.lastname: Giethlen
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Neill
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Søren M
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Mette N
authors.initials: MN
authors.lastname: Poulsen
authors.forename: John M
authors.initials: JM
authors.lastname: Schaus
authors.forename: Louise M
authors.initials: LM
authors.lastname: Witten
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D005466:Fluorocarbons
chemical_list: D001596:Benzylamines; D007211:Indoles; D010622:Phencyclidine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C568612:(2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine; D005466:Fluorocarbons; C097216:serotonin 6 receptor