Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors

In an effort to improve diazabicycloalkane-based opioid receptor ligands, N-3(6)-arylpropenyl-N-6(3)-propionyl-3,6-diazabicyclo[3.1.1]heptanes (3A,Ba-i) were synthesized and their affinity and selectivity towards mu-, delta- and kappa-receptors were evaluated. The results of the current study revealed a number of compounds (3Bb, 3Bg and 3Bh) having a high affinity for A (K-1 at mu-receptors ranging from 2.7 to 7.9 nM) versus 6 (K-i at delta-receptors &rt; 2000 nM) and versus kappa (K-i at kappa-receptors &rt; 5000 nM) receptors. Molecular modelling carried out on the pair 3Aa/3Ba and on the 3Bh was consistent with the hypothesis that the two series of compounds 3A and 3B interact with the mu-receptor in very different ways. (c) 2005 Elsevier Ltd. All rights reserved.