Synthesis, molecular modeling, and opioid receptor affinity of 9,10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0.0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2.1]octanes

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 mu opioid receptors. This h ypothesis, together with the remarkable analgesic properties observed for N -3 propionyl, N-8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the pi perazine moiety in order to identify derivatives with increased potency tow ard this receptor class. In the present report, we describe the synthesis o f the novel compounds 9,10-diazatricyclo[4.2.1.1(2.5)]decane (4) and 2,7-di azatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivati ves functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among th e compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibi ted the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.