3-(1-piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels

Bioorg Med Chem. 1998 Jun;6(6):743-53. doi: 10.1016/s0968-0896(98)00028-5.

Abstract

3-(4-Piperidinyl)-5-arylpyrazoles, such as 1, were selective for the cloned human dopamine D4 receptor (hD4), but also showed affinity at voltage sensitive calcium, sodium and potassium ion channels. A combination of substituent changes to reduce the basicity of the piperidine nitrogen and conformational restriction to give 4,5-dihydro-1H-benzo[g]indazoles reduced this ion channel affinity at the expense of selectivity for hD4 over other dopamine receptors. Incorporation of piperazine into the 4,5-dihydro-1H-benzo[g]indazoles in place of piperidine gave a novel series of high affinity, selective, orally bioavailable hD4 ligands, such as 16, with improved selectivity over ion channels.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • CHO Cells
  • Calcium Channels / metabolism
  • Cell Line
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / metabolism
  • Indazoles / pharmacokinetics
  • Ion Channel Gating
  • Ion Channels / metabolism*
  • Ligands
  • Muscle, Skeletal / metabolism
  • Potassium Channels / metabolism
  • Rabbits
  • Rats
  • Receptors, Dopamine D2 / biosynthesis
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D4
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / metabolism
  • Sodium Channels / metabolism
  • Structure-Activity Relationship

Substances

  • 3-(4-(2-(2-chlorophenyl)ethyl)-1-piperazinyl)-4,5-dihydro-1H-benzo(g)indazole
  • Calcium Channels
  • DRD4 protein, human
  • Drd4 protein, rat
  • Indazoles
  • Ion Channels
  • Ligands
  • Potassium Channels
  • Receptors, Dopamine D2
  • Recombinant Proteins
  • Sodium Channels
  • Receptors, Dopamine D4