| Title
| - Synthesis, Molecular Modeling, and Opioid Receptor Affinity of9,10-Diazatricyclo[4.2.1.12,5]decanes and 2,7-Diazatricyclo[4.4.0.03,8]decanesStructurally Related to 3,8-Diazabicyclo[3.2.1]octanes
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| Abstract
| - Various lines of evidence, including molecular modeling studies, imply that the endoethylenicbridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinitytoward μ opioid receptors. This hypothesis, together with the remarkable analgesic propertiesobserved for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), hasprompted us to insert an additional endoethylenic bridge on the piperazine moiety in order toidentify 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) and2,7-diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalizedat the two nitrogen atoms by propionyl and arylpropenyl groups (6a−e, 7a−d). Opioid receptorbinding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamylderivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7adisplayed in vivo (mice) an analgesic potency 6-fold that of morphine.
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