Characterization of 4‐(2‐hydroxyphenyl)‐1‐[2′‐[N‐(2″‐pyridinyl)‐p‐fluorobenzamido]ethyl]piperazine (p‐DMPPF) as a new potent 5‐HT1A antagonist

• Published in: British journal of pharmacology 2007-11, Vol.152 (6), p.952-958
• Main Authors: Defraiteur, C, Plenevaux, A, Scuvée‐Moreau, J, Rouchet, N, Goblet, D, Luxen, A, Seutin, V
• Format: Article
• Language: English
• Subjects: 5-HT1A antagonists; 5-HT1A receptors; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Aminopyridines - pharmacology; Animals; Benzamides - pharmacology; Binding, Competitive - drug effects; Biological and medical sciences; brain slices; dorsal raphe; Electrophysiology; Human health sciences; In Vitro Techniques; Kinetics; Male; Medical sciences; Neurons - drug effects; p-DMPPF; Pharmacie, pharmacologie & toxicologie; Pharmacology. Drug treatments; Pharmacy, pharmacology & toxicology; Piperazines - pharmacology; Protein Binding; Pyridines - pharmacology; Radioligand Assay; Raphe Nuclei - cytology; Raphe Nuclei - drug effects; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - drug effects; Research Papers; Sciences de la santé humaine; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707431

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‐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‐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‐DMPPFp‐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. British Journal of Pharmacology (2007) 152, 952–958; doi:10.1038/sj.bjp.0707431; published online 20 August 2007