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

Abstract Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1 2,5 ]decane ( 1a ) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.0 3,8 ]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.