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.