Further Studies on Arylpiperazinyl Alkyl Pyridazinones: Discovery of an Exceptionally Potent, Orally Active, Antinociceptive Agent in Thermally Induced Pain

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• 作者：Claudio Biancalani ; Maria Paola Giovannoni ; Stefano Pieretti ; Nicoletta Cesari ; Alessia Graziano ; Claudia Vergelli ; Agostino Cilibrizzi ; Amalia Di Gianuario ; Mariantonella Colucci ; Giorgina Mangano ; B
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 10, 2009
• 年：2009
• 卷：52
• 期：23
• 页码：7397-7409
• 全文大小：1081K
• 年卷期：v.52,no.23(December 10, 2009)
• ISSN：1520-4804

文摘

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 <b>6ab>, which showed an EDb>50b> = 3.5 μg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, <b>6ab> 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 <b>6ab> 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.