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

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.

• Authors: Margarita Valhondo, Isabel Marco, Mar Martín-Fontecha, Henar Vázquez-Villa, José A Ramos, Reinhard Berkels, Thomas Lauterbach, Bellinda Benhamú, María L López-Rodríguez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 20 Pg. 7851-61 (Oct 24 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 24050112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Analgesics (chemical synthesis, metabolism, 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, pharmacokinetics, pharmacology)
• Humans
• Hydantoins (chemical synthesis, pharmacokinetics, pharmacology)
• Kinetics
• Ligands
• Male
• Mice
• Models, Chemical
• Molecular Structure
• Pain (metabolism, prevention & control)
• Pain Measurement (methods)
• Piperazines (pharmacology)
• Pyridines (pharmacology)
• Radioligand Assay
• Rats
• Receptor, Serotonin, 5-HT1A (genetics, metabolism)
• Serotonin 5-HT1 Receptor Agonists (chemical synthesis, pharmacokinetics, pharmacology)
• Serotonin Antagonists (pharmacology)