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Related Experiment Videos

Indanyl piperazines as melatonergic MT2 selective agents.

Ronald J Mattson1, John D Catt, Daniel Keavy

  • 1Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA. mattsonr@bms.com

Bioorganic & Medicinal Chemistry Letters
|March 20, 2003
PubMed
Summary
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Researchers optimized a benzyl piperazine structure to create N-acyl-4-indanyl-piperazines. Compound 13, a selective MT(2) agonist, effectively advanced circadian rhythms in rats, similar to melatonin but with fewer vascular effects.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Chronobiology

Background:

  • Melatonergic receptors, particularly MT(2), play a crucial role in regulating circadian rhythms.
  • Developing selective ligands for MT(2) receptors is a key area in chronobiology and sleep research.
  • Benzyl piperazine scaffolds have shown potential in modulating melatonergic signaling.

Purpose of the Study:

  • To optimize the benzyl piperazine pharmacophore for high-affinity binding to melatonergic MT(2) receptors.
  • To synthesize and characterize novel N-acyl-4-indanyl-piperazines as potential MT(2) receptor modulators.
  • To evaluate the in vivo efficacy and selectivity of a lead compound in a preclinical model.

Main Methods:

  • Structure-activity relationship (SAR) studies were conducted on benzyl piperazine derivatives.

Related Experiment Videos

  • Synthesis of N-acyl-4-indanyl-piperazines, including the lead compound (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13).
  • In vivo studies in rats to assess circadian phase-shifting effects and ex vivo assessment of vascular activity.

    • Main Results:

    • Optimization yielded N-acyl-4-indanyl-piperazines with high affinity for MT(2) receptors.
    • Compound 13 demonstrated potent and selective MT(2) agonism, advancing circadian rhythm in rats at doses comparable to melatonin.
    • Compound 13 exhibited significantly weaker contractile effects on rat tail artery compared to melatonin, suggesting improved cardiovascular safety.

    Conclusions:

    • N-acyl-4-indanyl-piperazines represent a promising class of selective MT(2) receptor agonists.
    • Compound 13 is a water-soluble, selective MT(2) agonist with potential therapeutic applications for circadian rhythm disorders.
    • The distinct pharmacological profile of compound 13, particularly its reduced vascular effects, warrants further investigation.