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)