Orally Active Analogues of the Dopaminergic Prodrug 6-(N,N-Di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: Synthesis and Pharmacological Activity

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• 作者：Bastiaan J. Venhuis ; Durk Dijkstra ; David J. Wustrow ; Leonard T. Meltzer ; Lawrence D. Wise ; Stephen J. Johnson ; Thomas G. Heffner ; and Hå ; kan V. Wikströ ; m
• 刊名：Journal of Medicinal Chemistry
• 出版年：2003
• 出版时间：February 13, 2003
• 年：2003
• 卷：46
• 期：4
• 页码：584 - 590
• 全文大小：131K
• 年卷期：v.46,no.4(February 13, 2003)
• ISSN：1520-4804

文摘

A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one(6), an enone prodrug of the mixed DA D₁/D₂ agonist 5,6-diOH-DPAT (2), was synthesized.The pharmacological profiles of these new enones and their in vivo pharmacological activitieswere investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg^-1po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronouncedand long lasting pharmacological effects. The pharmacological profile of enone 12 was foundto be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01).Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence ofhydroxylated metabolites of the parent enones. It is speculated that such metabolites are '-hydroxylated enones that may constitute the first step in the formation of the correspondingcatechols.