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