Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists

摘要

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (K_i = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent [K_i = 0.0059 nM) K-opioid receptor agonist among the four stereoisomers Maj-3c produced significant antinociception (ED_(50) = 0.000406 mg kg~(-1)) compared to U-50.488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED_(50) = 0.000568 mg kg~(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist [K_i = 35.13 nM). More importantly, the dose for the sedative effect (ED_(50) = 9.29 mg kg~(-1)) of maj-lla was significantly higher than its analgesic dose (ED_(50) = 0.392 mg kg~(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.