Design and synthesis of long-chain arylpiperazines with mixed affinity for serotonin transporter (SERT) and 5-HT(1A) receptor

J Pharm Pharmacol. 2005 Oct;57(10):1319-27. doi: 10.1211/jpp.57.10.0011.

Abstract

A new generation of antidepressant agents could be represented by compounds with mixed activity as serotonin transporter (SERT) inhibitors and 5-HT(1A) receptor antagonists. We report here on the synthesis and evaluation of SERT and 5-HT(1A) receptor affinity of long-chain arylpiperazines obtained either by modifying 6-nitroquipazine into a long-chain arylpiperazine or by inserting a modified 6-nitroquipazine moiety or other structures endowed with SERT affinity into a long-chain arylpiperazine with 5-HT(1A) affinity. Among the compounds studied, 2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-(6-nitro-2-quinolyl)ethylamine (21) and 1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-propanone (24) showed good affinity values for SERT and 5-HT(1A) receptors (SERT: K(i) (inhibition constant)=71.8 and 62.8 nM; 5-HT(1A)K(i)=14.2 and 0.82 nM, respectively).

MeSH terms

  • Animals
  • Binding, Competitive
  • Drug Design*
  • Ethylamines / chemical synthesis
  • Ethylamines / pharmacology
  • Guinea Pigs
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Ileum / drug effects
  • Ileum / metabolism
  • Male
  • Naphthalenes / chemical synthesis
  • Naphthalenes / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Propane / analogs & derivatives
  • Propane / chemical synthesis
  • Propane / pharmacology
  • Pyridines / pharmacology
  • Quipazine / analogs & derivatives
  • Quipazine / chemistry
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / pharmacology
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Receptor Agonists / pharmacology
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tritium

Substances

  • 1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-1-propanone
  • 2-(4-(2-methoxyphenyl)piperazin-1-yl)-N-(6-nitro-2-quinolyl)ethyamine
  • Ethylamines
  • Naphthalenes
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Tritium
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Quipazine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 6-nitroquipazine
  • Propane