4-(2'-Methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] piperazine and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine, two new antagonists at pre- and postsynaptic serotonin-1A receptors.

p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido] ethylpiperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine] competitively antagonized 5-HT1A receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited to partial agonist activity on any of these measures. When given i.p., p-MPPI and p-MPPF dose-dependently antagonized the hypothermia induced by 8-hydroxy-2- (di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg), with approximate ID50 of 5 and 3 mg/kg, respectively. The inhibitory effect caused by a fixed dose of p-MPPI (6 mg/kg) or p-MPPF (3 mg/kg) was surmounted by higher doses of 8-OH-DPAT. p-MPPI and p-MPPF also attenuated the hypothermia induced by gepirone. Forepaw treading caused by 8-OH-DPAT (2 mg/kg) in reserpine-pretreated rats (1 mg/kg, s.c., 18-24 hr before the experiment) was dose-dependently antagonized by p-MPPI and p-MPPF with approximate ID50 of 3 and 0.7 mg/kg, respectively. p-MPPI also antagonized forepaw treading induced by 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) (5 mg/kg) and this antagonism was competitively overcome by higher doses of 5-methoxy-N,N,-dimethyltryptamine. p-MPPI and p-MPPF were able to antagonize the 8-OH-DPAT-(0.5 mg/kg) induced reduction in the 5-HIAA/5-HT ratio, a measure of 5-HT turnover in the hippocampus or striatum. No hypothermia or reciprocal forepaw treading was produced by either drug when given at doses as high as 10 mg/kg. Neither p-MPPI nor p-MPPF (10 mg/kg) given alone significantly altered the ratio of 5-HIAA/5-HT in the hippocampus or striatum. Also, binding of [3H]p-MPPF to hippocampal membranes was unaltered by the addition of 100 microM guanylyl-imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors.