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

R. J. Thielen, N. B. Fangon, Alan Frazer

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Abstract

p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-iodo- benzamido]ethyl]piperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2''- pyridinyl)-p-fluorobenzamido]ethyl]piperazine] competitively antagonized 5- HT(1A) receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited no 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 100μM guanylyl- imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT(1A) receptors and somatodendritic 5-HT(1A) autoreceptors.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number2
StatePublished - 1996

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Receptor, Serotonin, 5-HT1A
8-Hydroxy-2-(di-n-propylamino)tetralin
Serotonin
Methoxydimethyltryptamines
Induced Hypothermia
Hydroxyindoleacetic Acid
Hypothermia
Hippocampus
Guanylyl Imidodiphosphate
4-(2' methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine
piperazine
4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine
Autoreceptors
Reserpine
Membranes
hydroxide ion

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{1ede16b1838c4c81a3ca205bfa100ada,
title = "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",
abstract = "p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-iodo- benzamido]ethyl]piperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2''- pyridinyl)-p-fluorobenzamido]ethyl]piperazine] competitively antagonized 5- HT(1A) receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited no 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 100μM guanylyl- imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT(1A) receptors and somatodendritic 5-HT(1A) autoreceptors.",
author = "Thielen, {R. J.} and Fangon, {N. B.} and Alan Frazer",
year = "1996",
language = "English (US)",
volume = "277",
pages = "661--670",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - 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

AU - Thielen, R. J.

AU - Fangon, N. B.

AU - Frazer, Alan

PY - 1996

Y1 - 1996

N2 - p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-iodo- benzamido]ethyl]piperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2''- pyridinyl)-p-fluorobenzamido]ethyl]piperazine] competitively antagonized 5- HT(1A) receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited no 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 100μM guanylyl- imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT(1A) receptors and somatodendritic 5-HT(1A) autoreceptors.

AB - p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-iodo- benzamido]ethyl]piperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2''- pyridinyl)-p-fluorobenzamido]ethyl]piperazine] competitively antagonized 5- HT(1A) receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited no 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 100μM guanylyl- imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT(1A) receptors and somatodendritic 5-HT(1A) autoreceptors.

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