Conformationally restricted bicyclic KOR agonists 10 with an endo-configured amino moiety were synthesized to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2-5. A seven-step synthesis starting with (S)-configured 4-oxopiperidine-2-carboxylate 13 was developed. cis- and trans-configured diesters 12 were obtained in a 3 : 1 ratio via hydrogenation of the α,β-unsaturated ester 14. After establishment of the bicyclic scaffold, a diastereoselective reductive amination of ketone 11 provided exclusively the endo-configured bicyclic amines 10a,b. The 3 : 1 mixtures of enantiomers were separated by chiral HPLC, respectively, leading to enantiomerically pure KOR agonists (1S,5S,7R)-10a,b and (1R,5R,7S)-10a,b (ent-10a,b). The KOR affinity was determined in receptor binding studies with the radioligand [3H]U-69 593. The high KOR affinity of endo-configured amines 10a (Ki = 7 nM) and 10b (Ki = 13 nM) indicates that the dihedral angle of the KOR pharmacophoric element N(pyrrolidine)-C-C-N(phenylacetyl) of 42° is close to the bioactive conformation of more flexible KOR agonists. It should be noted that changing the configuration of potent and selective KOR agonists 10a and 10b led to potent and selective σ1 ligands (e.g. ent-10aKi(σ1) = 10 nM).