Synthesis and Opioid Activity of Enantiomeric N-Substituted 2,3,4,4a,5,6,7, 7a-Octahydro-1H-benzofuro[3,2-e]isoquinolines

A series of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines was synthesized. The (-)-enantiomers had much greater κ-, μ-, and δ-opioid receptor binding affinity than the corresponding (+)-enantiomers. Compounds (-)-1a, (-)-1b, and (-)-1c displayed subnanomolar binding affinity for the μ-receptor, and (-)-1b had a high affinity for the κ-receptor. Compound (—)—la was a μ-partial agonist and κ-antagonist. Compound (-)-1b was a potent neutral μ-antagonist (K d = 0.22 nM) and a κ-partial agonist.