Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: Part 1

The observation that 17-cyclopropylmethylmorphinan derivatives without the 4,5-epoxy ring showed more κ selectivity than those with a 4,5-epoxy ring led us to develop a working hypothesis: the position of the plane composed of the A and B rings would influence the opioid receptor type selectivity and that the decrease in the torsion angle C11–C12–C13–C14 could improve the κ selectivity. Consistent with our hypothesis, KNT-42 with an N-cyclopropylmethyl propellane structure, whose A and B rings were fixed in a torsion angle of approximately 0°, showed κ selective agonist activity.

Graphical abstractPropellane derivative KNT-42 showed rather κ selective agonist activity.Figure optionsDownload full-size imageDownload as PowerPoint slide