SELECTIVE KAPPA-OPIOID AGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PIPERIDINES INCORPORATING AN OXO-CONTAINING ACYL GROUP

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using K-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED(50)s of 0.47 and 0.73 mu mol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective K-agonists, has a reduced propensity to cause a number of K-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED(50) Of 26.5 mu mol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.