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Defraiteur C, Plenevaux A, Scuvee-Moreau J, Rouchet N, Goblet D, Luxen A, Seutin V: Characterization of 4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido] ethyl] piper azine (p-DMPPF) as a new potent 5-HT1A antagonist. Br J Pharmacol. 2007 Nov;152(6):952-8. Epub 2007 Aug 20.
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-HT (1A) receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido] ethyl] pipe razine) with that of the well-known 5-HT (1A) 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] pipe razine). 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-HT (1A) agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-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-HT (1A) 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> or=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-HT (1A) 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-HT (1A) antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT (1A) receptors makes it a good candidate for clinical development. |
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