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: Jorn Arnt, Benny Bang-Andersen, Ben Grayson, Franklin P Bymaster, Michael P Cohen, Neil W DeLapp, Bruno Giethlen, Mads Kreilgaard, David L McKinzie, Joanna C Neill, David L Nelson, Søren M Nielsen, Mette N Poulsen, John M Schaus, Louise M Witten
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 13 Issue 8 Pg. 1021-33 (Sep 2010) ISSN: 1469-5111 [Electronic] England
• PMID: 20569520 (Publication Type: Comparative Study, Journal Article)

Chemical References

• (2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine
• Benzylamines
• Indoles
• Receptors, Serotonin
• Serotonin Antagonists
• serotonin 6 receptor
• Phencyclidine

Topics

• Animals
• Benzylamines (chemistry, metabolism, therapeutic use)
• Cells, Cultured
• Cognition Disorders (chemically induced, drug therapy, metabolism)
• Cricetinae
• Dose-Response Relationship, Drug
• HEK293 Cells
• Humans
• Indoles (chemistry, metabolism, therapeutic use)
• Male
• Phencyclidine (administration & dosage, toxicity)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (metabolism)
• Recognition, Psychology (drug effects, physiology)
• Serotonin Antagonists (chemistry, metabolism, therapeutic use)