Characterization of 4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-DMPPF) as a new potent 5-HT1A antagonist.
OBJECTIVE
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]piperazine) 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]piperazine).


METHODS
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.


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
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.
Defraiteur
C
C
Cyclotron Research Center, Liege University, Liege, Belgium.
Plenevaux
A
A
Scuvée-Moreau
J
J
Rouchet
N
N
Goblet
D
D
Luxen
A
A
Seutin
V
V
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D004594:Electrophysiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
C513932:4-(2'-hydroxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine; D000631:Aminopyridines; D001549:Benzamides; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C099463:4-(2' methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine
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