Synthesis and 5-HT3 receptor agonist activity of arylureas derived from histamine.

1 In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2 IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-amethylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2=9.12+0.06, Schild slope: 1.0 0.1, n=8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 ± 0.2). histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor. 7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in a pD2 value of 4.72 ± 0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 value of 7.1 ± 0.1 (n = 9). Similarly ondansetron antagonized the contractions evoked by the 5-HT3 receptor agonist, 2-methyl-5-HT with a pA2 value of 7.3 ± 0.1 (n = 4). IPP and thioperamide did not mimic 2-methyl-5-HT but non-competitively inhibited the 2-methyl-5-HT-induced contractions of this preparation. 8 In an in vivo model for 5-HT3 activity, the Von Bezold Jarisch reflex, thioperamide showed antagonism in low dosages, which correlated well with the affinity for the 5-HT3 receptor site. Yet, at higher dosages no further 5-HT3 receptor antagonism was observed. For IPP no 5-HT3 receptor activity could be observed in vivo. 9 In the present study we showed that many H3 receptor compounds, that are regarded as highly selective (including the prototype drug, thioperamide), also interact with the 5-HT3 receptor, albeit at higher drug concentrations.

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“…The arylurea analogues of histamine are reported to be quite potent 5-HT3 receptor agonists (Bermudez et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the receptor selectivity of the H₃ receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT₃ receptor revealed

Leurs

Tulp

Menge

et al. 1995

British J Pharmacology

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N-(Quinuclidin-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide: a high affinity 5-HT3 receptor partial agonist

Clark¹,

Muchowski²,

Weinhardt³

et al. 1995

Bioorganic & Medicinal Chemistry Letters

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New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT 3 ) receptor agonists for the treatment of constipation

Imanishi¹,

Iwaoka²,

Koshio³

et al. 2003

Bioorganic & Medicinal Chemistry

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Synthesis and 5-HT3 receptor agonist activity of arylureas derived from histamine.

Cited by 3 publications

References 8 publications

Evaluation of the receptor selectivity of the H₃ receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT₃ receptor revealed

Evaluation of the receptor selectivity of the H₃ receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT₃ receptor revealed

N-(Quinuclidin-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide: a high affinity 5-HT3 receptor partial agonist

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT 3 ) receptor agonists for the treatment of constipation

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Synthesis and 5-HT3 receptor agonist activity of arylureas derived from histamine.

Cited by 3 publications

References 8 publications

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed

N-(Quinuclidin-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide: a high affinity 5-HT3 receptor partial agonist

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT 3 ) receptor agonists for the treatment of constipation

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Evaluation of the receptor selectivity of the H₃ receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT₃ receptor revealed

Evaluation of the receptor selectivity of the H₃ receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT₃ receptor revealed