Synthesis of novel diazatricyclodecanes (DTDs). Effects of structural variation at the C3′ allyl end and at the phenyl ring of the cinnamyl chain on μ-receptor affinity and opioid antinociception

Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.12,5]decane (1a) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.03,8]decane (2a), in which the cinnamyl moiety was replaced by various aralkenyl chains, 1b-l and 2b-l, respectively, have been synthesized and evaluated for their ability to bind to the opioid μ-, δ- and κ-receptors. The binding data indicated that compounds 1b,d,e,h and 2b,d,e,f,h,i showed a μ-affinity in the low nanomolar range with moderate or negligible affinity towards δ- and κ-receptors. Selected DTDs, the pairs 1,2b, 1,2e and 1,2h, were also evaluated for analgesic effect. In the hot plate test, only 1b given ip was found to have similar opioid antinociception and chronic tolerance as morphine.