Synthesis and binding affinity of cis-(-)- and cis-(+)-N-ethyleneamino-N-nordeoxymetazocine and cis-(-)-N-normetazocine analogues at sigma(1), sigma(2), and kappa opioid receptors

The synthesis of cis-(+)- and cis-(-)-N-ethyleneamino-N-nordeoxymetazocine and cis-(-)-N-normetazocine analogues is described and their affinities to sigma (1), sigma (2), and kappa opioid receptors are evaluated. The cis-(+) -deoxy compounds displayed high sigma/kappa selectivity with nanomolar K-i values for sigma (1) receptors, whereas in the cis-(-)-N-normetazocine seri es the compound (-)-7b was found to bind with nanomolar affinity to the kap pa opioid receptor (K-i = 21.5 nM). Compound (-)-7b showed good selectivity for the kappa opioid receptor in comparison to the sigma (1), and sigma (2 ), sites and to the mu and delta opioid receptors. A correlation of the bin ding affinities between cis-(-)- and cis-(+)-N-deoxynormetazocine derivativ es show that both isomers of the deoxy analogs have similar sigma (1) and s igma (2) binding profiles as the cis-(+)-N-normetazocine derivatives. (C) 2 001 Elsevier Science B.V. All rights reserved.