New κ-Receptor Agonists Based upon a 2-piperidine Nucleus

Article abstract of DOI:10.1021/jm00081a009

The syntheses of some 1-<(3,4-dichlorophenyl)acetyl>-2-<(alkylamino)methyl>piperidines and their activities as κ-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 κ-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, κ-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-dioxa-8-azaspiro<4.5>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 κ-opioid receptors over both μ- and δ-opioid receptor subtypes.