Effects of novel 5-HT1A receptor antagonists on measures of post-synaptic 5-HT1A receptor activation in vivo

The effects of two putative 5-HT1A antagonists, 4-(2'-methoxyphenyl)-1- [2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine (p-MPPF), were examined in vivo in two tests of postsynaptic 5-HT1A receptor activation, hypothermia and reciprocal forepaw treading, in the rat. Both p-MPPI (10 mg/kg, i.p.) and p-MPPF (10 mg/kg, i.p.) antagonized the hypothermia induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg, s.c.). Neither p-MPPI nor p-MPPF administered alone at a dose of 10 mg/kg (i.p.) induced hypothermia. Similarly, both p-MPPI (10 mg/kg, i.p.) and p-MPPF (2.5 mg/kg, i.p.) completely antagonized 8-OH-DPAT (2 mg/kg, s.c.)-induced forepaw treading in rats pretreated with reserpine (1 mg/kg, s.c., 18-24 hours prior to the experiment). p-MPPI and p-MPPF, at doses of 10 mg/kg (i.p.) did not induce forepaw treading in reserpine pretreated animals. The results of the present study demonstrate that p-MPPI and p-MPPF act as 5-HT1A receptor antagonists in these measures of postsynaptic 5-HT1A receptor activation.