| Autor: |
Arnt, Jorn, Bang-Andersen, Benny, Grayson, Ben, Bymaster, Franklin P., Cohen, Michael P., DeLapp, Neil W., Giethlen, Bruno, Kreilgaard, Mads, McKinzie, David L., Joanna C.6Neill, Nelson, David L., Nielsen, Søren M., Mette N.6Poulsen, Schaus, John M., Witten, Louise M. |
| Předmět: |
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| Zdroj: |
International Journal of Neuropsychopharmacology; Sep2010, Vol. 13 Issue 8, p1021-1033, 13p |
| Abstrakt: |
The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT6R 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-HT6 receptor (5-HT6R) with a Ki of 0.83 nM. In a 5-HT6 GTPcS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic a1A- and a1B-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-HT6 antagonist radioligand [³H]Lu AE60157 ([³H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED50 of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT6R occupancy time-course experiment indicated a plasma EC50 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-HT6R 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-HT6Rs 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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