Exploring the importance of piperazine N-atoms for sigma(2) receptor affinity and activity in a series of analogs of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28)

J Med Chem. 2009 Dec 10;52(23):7817-28. doi: 10.1021/jm9007505.

Abstract

sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms was alternatively replaced by a methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential for sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma(2)K(i) = 0.68, sigma(1)K(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K(i) = 0.11 nM) and noteworthy() selective (1627-fold) sigma(1) ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K(i) = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2) agonists (EC(50)s 1.40 and 3.64 muM respectively) more potent than 7.

MeSH terms

  • Amides / chemistry
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Guinea Pigs
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Male
  • Naphthalenes / chemistry*
  • Naphthalenes / metabolism*
  • Naphthalenes / pharmacology
  • Nitrogen / chemistry*
  • Piperazines / chemistry*
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Rats
  • Receptors, sigma / agonists
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / metabolism*
  • Steroid Isomerases / metabolism
  • Structure-Activity Relationship

Substances

  • 1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl)-piperazine
  • Amides
  • Ligands
  • Naphthalenes
  • Piperazines
  • Receptors, sigma
  • sigma-2 receptor
  • Steroid Isomerases
  • EBP protein, human
  • Nitrogen