Syntheses and binding studies of new [(aryl)(aryloxy)methyl]piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5-HT) and norepinephrine (NE) transporters

J Med Chem. 2003 Dec 4;46(25):5512-32. doi: 10.1021/jm0309349.

Abstract

In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / chemical synthesis*
  • Adrenergic Uptake Inhibitors / chemistry
  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology
  • Brain / metabolism
  • Carrier Proteins / metabolism*
  • Fluoxetine / analogs & derivatives*
  • Fluoxetine / chemistry
  • In Vitro Techniques
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Morpholines / chemistry
  • Nerve Tissue Proteins*
  • Norepinephrine / metabolism
  • Norepinephrine Plasma Membrane Transport Proteins
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Reboxetine
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Stereoisomerism
  • Structure-Activity Relationship
  • Symporters / metabolism*

Substances

  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents
  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Morpholines
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a2 protein, rat
  • Slc6a4 protein, rat
  • Symporters
  • Fluoxetine
  • Receptor, Serotonin, 5-HT1A
  • nisoxetine
  • Serotonin
  • Reboxetine
  • Norepinephrine