Synthesis and evaluation of novel peripherally restricted κ-opioid receptor agonists

A series of 3-substituted analogs (3) of the parent κ agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human κ opioid receptor with high affinity (Ki = 0.31–9.5 nM) and were selective for κ over μ and δ opioid receptors. Compounds 3c, d, and 3g–i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral κ agonist ICI 204448.