Vianello, Paola and Albinati, Alberto and Pinna, Gérard Aimé and Lavecchia, Antonio and Marinelli, Luciana and Borea, Pier Andrea and Gessi, Stefania and Fadda, Paola and Tronci, Silvia and Cignarella, Giorgio (2000) Synthesis, molecular modeling, and opioid receptor affinity of 9,10-diazatricyclo[220.127.116.11,5]decanes and 2,7-diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8-diazabicyclo[3.2.1]octanes. Journal of Medicinal Chemistry, Vol. 43 (11), p. 2115-2123. eISSN 1520-4804. Article.
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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[18.104.22.168,5]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.
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