Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes

Paola Vianello, Alberto Albinati, Gerardo A. Pinna, Antonio Lavecchia, Luciana Marinelli, Pier Andrea Borea, Stefania Gessi, Paola Fadda, Silvia Tronci, Giorgio Cignarella

Research output: Contribution to journalArticle

Abstract

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.12,5]decane (4) and 2,7- diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

Original languageEnglish
Pages (from-to)2115-2123
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number11
DOIs
Publication statusPublished - Jun 1 2000

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ASJC Scopus subject areas

  • Organic Chemistry

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