A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED50=3.5 μg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, 6a was 4-fold more potent than morphine in the same test, suggesting a significant bioavailability. The same compound also showed high potency in the hot plate test. The antinociceptive effect of 6a was completely reversed by pretreatment with yohimbine both in the hot plate test and in the tail flick test. This demonstrated the involvement of the adrenergic system, which was confirmed by in vitro radioligand binding studies.

Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent, orally active, antinociceptive agent in thermally induced pain / C. BIANCALANI; M.P.GIOVANNONI; S.PIERETTI; N.CESARI; A.GRAZIANO; C.VERGELLI; A.CILIBRIZZI; A.DI GIANUARIO; M.COLUCCI; G.MANGANO; B.GARRONE; L.POLENZANI; V.DAL PIAZ. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - ELETTRONICO. - 52:(2009), pp. 7397-7409.

Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent, orally active, antinociceptive agent in thermally induced pain.

GIOVANNONI, MARIA PAOLA;VERGELLI, CLAUDIA;DAL PIAZ, VITTORIO
2009

Abstract

A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED50=3.5 μg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, 6a was 4-fold more potent than morphine in the same test, suggesting a significant bioavailability. The same compound also showed high potency in the hot plate test. The antinociceptive effect of 6a was completely reversed by pretreatment with yohimbine both in the hot plate test and in the tail flick test. This demonstrated the involvement of the adrenergic system, which was confirmed by in vitro radioligand binding studies.
2009
52
7397
7409
C. BIANCALANI; M.P.GIOVANNONI; S.PIERETTI; N.CESARI; A.GRAZIANO; C.VERGELLI; A.CILIBRIZZI; A.DI GIANUARIO; M.COLUCCI; G.MANGANO; B.GARRONE; L.POLENZANI; V.DAL PIAZ
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/372772
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