![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
MJ Millan, JM Rivet, H Canton, F Lejeune, K Bervoets, M Brocco, A Gobert, B Lefebvre de Ladonchamps, S Le Marouille-Girardon and L Verriele
Neurobiology Division, Institut de Recherches Servier, Paris, France.
The interaction at 5-hydroxytryptamine (5-HT) receptors of the novel naphtylpiperazine, S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine), was compared to that of the 5-HT1A ligands, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH- DPAT), WY 50,324 [N-(29(4-(2-pyrimidinyl)-1- piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) )- decane-1-carboxamide], (+)- flesinoxan, buspirone and BMY 7378 [(8-[2-[4-(2-methoxyphenyl)- 1- piperazinyl]ethyl]-8-azaspirol[-4-]-decane-7,9-dione 2HCl]. S 14671 showed a very high affinity for 5-HT1A sites (pKi, 9.3) as compared to the reference ligands (pKi values, 9.2, 8.7, 8.7, 7.9 and 8.7, respectively). S 14671 bound in an apparently competitive manner and, in distinction to the reference compounds, possessed a Hill Coefficient (1.4) significantly superior to 1. Although showing low affinity at 5- HT1B and 5-HT3 sites, S 14671 displayed significant affinity at both 5- HT1C and 5-HT2 sites; pKi, 7.8 in each case. Furthermore, S 14671 acted as an antagonist of 5-HT-stimulated phosphoinositide turnover in rat choroid plexus (5-HT1C) and cortex (5-HT2). In vivo, upon s.c. administration, S 14671 acted as a high efficacy agonist in models of 5- HT1A receptor-mediated activity: induction of flat-body posture, spontaneous tail-flicks, hypothermia and corticosterone secretion and inhibition of morphine-induced antinociception. In every test, S 14671 was the most potent compound: it was active at doses as low as 5 micrograms/kg s.c. Relative potency across all tests was S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than (+)- flesinoxan greater than buspirone with BMY 7378 too weak for comparison to be meaningful. The action of S 14671 in 5-HT1A tests was blocked by BMY 7378 and the 5-HT1A antagonist, (-)-alprenolol, but unaffected by the 5-HT1C/2 antagonist, ritanserin, and the 5-HT3 antagonist, ondansetron. Activation of postsynaptic 5-HT1A receptors was confirmed in 5,7-dihydroxytryptamine-lesioned rats, in which the potency of S 14671 to elicit spontaneous tail-flicks was potentiated. Activation of presynaptic receptors was demonstrated by inhibition of the electrical activity of the dorsal raphe nucleus with the following order of relative potency: S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than BMY 7378 greater than buspirone. Spiperone, which acts as a pure 5-HT1A antagonist at raphe 5-HT1A receptors, blocked the action of S 14671. In conclusion, S 14671 is a structurally novel ligand manifesting high efficacy and exceptional potency at both pre- and postsynaptic 5-HT1A receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
This article has been cited by other articles:
|
|
 |
|
  G. Pineyro and P. Blier Autoregulation of Serotonin Neurons: Role in Antidepressant Drug Action Pharmacol. Rev., September 1, 1999; 51(3): 533 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Koek, J.-F. Patoiseau, M.-B. Assié, C. Cosi, M. S. Kleven, E. Dupont-Passelaigue, E. Carilla-Durand, C. Palmier, J.-P. Valentin, G. John, et al. F 11440, a Potent, Selective, High Efficacy 5-HT1A Receptor Agonist with Marked Anxiolytic and Antidepressant Potential J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 266 - 283. [Abstract] [Full Text]
|
|
|
|
|
|
J. De Vry, R. Schohe-Loop, H.-G. Heine, J. M. Greuel, F. Mauler, B. Schmidt, H. Sommermeyer, and T. Glaser Characterization of the Aminomethylchroman Derivative BAY × 3702 as a Highly Potent 5-Hydroxytryptamine1A Receptor Agonist J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 1082 - 1094. [Abstract] [Full Text]
|
|
|
|
|
|
D. L. Willins and H. Y. Meltzer Direct Injection of 5-HT2A Receptor Agonists into the Medial Prefrontal Cortex Produces a Head-Twitch Response in Rats J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 699 - 706. [Abstract] [Full Text]
|
|
|
|
|
|
M. S. Kleven, M.-B. Assié, and W. Koek Pharmacological Characterization of In Vivo Properties of Putative Mixed 5-HT1A Agonist/5-HT2A/2C Antagonist Anxiolytics. II. Drug Discrimination and Behavioral Observation Studies in Rats J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 747 - 759. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Millan, S. Hjorth, R. Samanin, R. Schreiber, R. Jaffard, B. De Ladonchamps, S. Veiga, B. Goument, J.-L. Peglion, M. Spedding, et al. S 15535, A Novel Benzodioxopiperazine Ligand of Serotonin (5-HT)1A Receptors: II. Modulation of Hippocampal Serotonin Release in Relation to Potential Anxiolytic Properties J. Pharmacol. Exp. Ther., July 1, 1997; 282(1): 148 - 161. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
