New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus

J Med Chem. 1992 Feb 7;35(3):490-501. doi: 10.1021/jm00081a009.


The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Animals
  • Cricetinae
  • In Vitro Techniques
  • Male
  • Mice
  • Rabbits
  • Rats
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid, kappa
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology


  • Analgesics
  • Receptors, Opioid
  • Receptors, Opioid, kappa