Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites

Bioorg Med Chem. 2002 Dec;10(12):4091-102. doi: 10.1016/s0968-0896(02)00348-6.

Abstract

A series of (bisarylmethoxy)butylpiperidine derivatives was prepared and evaluated in vitro and in vivo to determine the structural requirements necessary for dual activity at the DAT and DA/5-HT receptor sites. These hybrid ligands, constructed by combining pharmacophores specific for the DAT and DA/5-HT receptors, could be useful drugs for treating cocaine addiction by assisting cocaine addicts in maintaining abstinence. The series was evaluated in vitro for DAT and DA/5-HT receptor activity and then selected compounds were tested in vivo for their effects on cocaine-induced hyperlocomotor activity (LMA). The majority of the new compounds demonstrated high to moderate affinity (4-191 nM) for the DAT with 4-hydroxy-4-phenylpiperidine analogues 14 and 15 possessing the greatest affinity. Compounds 15 and 22 exhibited the highest ratio of reuptake inhibition-to-binding (discrimination ratio, DR), 111 and 323, respectively. These derivatives had modest affinity and antagonistic activity for dopamine D(2)/D(3) receptors. Compounds 9 and 15 (DR=0.9 and 111, respectively) stimulated locomotor activity, whereas the other compounds suppressed this response. All compounds tested except for 17 and 21 attenuated cocaine-induced hyperlocomotion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / drug therapy
  • Cocaine-Related Disorders / prevention & control
  • Dopamine Antagonists / chemical synthesis
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / pharmacology
  • Dopamine Plasma Membrane Transport Proteins
  • Humans
  • Hyperkinesis / chemically induced
  • Hyperkinesis / drug therapy
  • Ligands
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Proteins / chemistry
  • Mice
  • Motor Activity / drug effects
  • Nerve Tissue Proteins*
  • Neurotransmitter Uptake Inhibitors / chemical synthesis*
  • Neurotransmitter Uptake Inhibitors / chemistry
  • Neurotransmitter Uptake Inhibitors / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, Dopamine / chemistry*
  • Receptors, Serotonin / chemistry
  • Structure-Activity Relationship

Substances

  • Dopamine Antagonists
  • Dopamine Plasma Membrane Transport Proteins
  • Ligands
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Uptake Inhibitors
  • Piperidines
  • Receptors, Dopamine
  • Receptors, Serotonin
  • SLC6A3 protein, human
  • Slc6a3 protein, mouse
  • Slc6a3 protein, rat
  • Cocaine