Reference : Characterization of 4-(2-hydroxyphenyl)-1-[2 '-[N-(2 ''-pyridinyl)-p-fluorobenzamido]eth...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/5146
Characterization of 4-(2-hydroxyphenyl)-1-[2 '-[N-(2 ''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-DMPPF) as a new potent 5-HT1A antagonist
English
Defraiteur, Caroline [Université de Liège - ULg > > Centre de recherches du cyclotron >]
Plenevaux, Alain mailto [Université de Liège - ULg > > Centre de recherches du cyclotron >]
Scuvée-Moreau, Jacqueline mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie - Département des sciences biomédicales et précliniques >]
Rouchet, Nathalie mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
Goblet, David mailto [Université de Liège - ULg > > Centre de recherches du cyclotron >]
Luxen, André mailto [Université de Liège - ULg > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron >]
Seutin, Vincent mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
Nov-2007
British Journal of Pharmacology
Nature Publishing Group
152
6
952-958
Yes (verified by ORBi)
International
0007-1188
London
[en] brain slices ; 5-HT1A receptors ; 5-HT1A antagonists ; dorsal raphe ; p-DMPPF
[en] Background and purpose: The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT1A receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]-ethyl] piperazine) with that of the well-known 5-HT1A antagonists, WAY-100635(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4-(2-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)p-fluorobenzamido] ethyl] piperazine). Experimental approach: Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT1A agonist, 8-OH-DPAT [8-hydroxy-2-(di-npropylamino)tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays. Key results: Consistently with a 5-HT1A receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635 > p-DMPPF >= p-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT1A receptors, with a K-i value of 7 nM on these receptors. Conclusions and implications: The potency of the new compound, p-DMPPF, as a 5-HT1A antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT1A receptors makes it a good candidate for clinical development.
Researchers ; Professionals
http://hdl.handle.net/2268/5146
10.1038/sj.bjp.0707431

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