New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo

J Med Chem. 2013 Oct 24;56(20):7851-61. doi: 10.1021/jm400766k. Epub 2013 Oct 8.

Abstract

We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2-ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (Ki = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ∼ 3 h and CLint = 3.5 mL/min/kg, at 5 μM), and a low level of protein binding (25%, at 5 μM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Binding, Competitive / drug effects
  • Cyclic AMP / metabolism
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • HeLa Cells
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Hydantoins / chemical synthesis
  • Hydantoins / pharmacokinetics
  • Hydantoins / pharmacology
  • Kinetics
  • Ligands
  • Male
  • Mice
  • Models, Chemical
  • Molecular Structure
  • Pain / metabolism
  • Pain / prevention & control*
  • Pain Measurement / methods
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis*
  • Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Serotonin Antagonists / pharmacology

Substances

  • 2-(4-((2-(2-ethoxyphenoxy)ethyl)amino)butyl)tetrahydro-1H-pyrrolo(1,2-c)imidazole-1,3(2H)-dione
  • Analgesics
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Hydantoins
  • Ligands
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Cyclic AMP
  • Cytochrome P-450 CYP2D6