New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo.
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.
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid , E-28040 Madrid, Spain.
Margarita
M
Valhondo
Isabel
I
Marco
Mar
M
Martín-Fontecha
Henar
H
Vázquez-Villa
José A
JA
Ramos
Reinhard
R
Berkels
Thomas
T
Lauterbach
Bellinda
B
Benhamú
María L
ML
López-Rodríguez
D000700:Analgesics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D010146:Pain / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
C586835:2-(4-((2-(2-ethoxyphenoxy)ethyl)amino)butyl)tetrahydro-1H-pyrrolo(1,2-c)imidazole-1,3(2H)-dione; D000700:Analgesics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D006827:Hydantoins; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000242:Cyclic AMP; D019389:Cytochrome P-450 CYP2D6