title: S 14671: a naphtylpiperazine 5-hydroxytryptamine1A agonist of exceptional potency and high efficacy possessing antagonist activity at 5-hydroxytryptamine1C/2 receptors.
abstract: 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)
authors.affiliation: Neurobiology Division, Institut de Recherches Servier, Paris, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: J M
authors.initials: JM
authors.lastname: Rivet
authors.forename: H
authors.initials: H
authors.lastname: Canton
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: K
authors.initials: K
authors.lastname: Bervoets
authors.forename: M
authors.initials: M
authors.lastname: Brocco
authors.forename: A
authors.initials: A
authors.lastname: Gobert
authors.forename: B
authors.initials: B
authors.lastname: Lefebvre de Ladonchamps
authors.forename: S
authors.initials: S
authors.lastname: Le Marouille-Girardon
authors.forename: L
authors.initials: L
authors.lastname: Verriele
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000698:Analgesia; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011187:Posture; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010716:Phosphatidylinositols; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C073650:S 14671; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone