RT Journal Article
T1 New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo
A1 Valhondo Falcón, Margarita
A1 Marco, Isabel
A1 Martín-Fontecha Corrales, María Del Mar
A1 Vázquez Villa, María Del Henar
A1 Ramos Atance, José Antonio
A1 Berkels, Reinhard
A1 Lauterbach, Thomas
A1 Benhamú Salama, Bellinda
A1 López Rodríguez, María Luz
AB 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.
PB ACS Publications
SN 0022-2623
YR 2013
FD 2013-10-24
LK https://hdl.handle.net/20.500.14352/114421
UL https://hdl.handle.net/20.500.14352/114421
LA eng
NO Valhondo, M., Marco, I., Martín-Fontecha, M., Vázquez-Villa, H., Ramos, J. A., Berkels, R., Lauterbach, T., Benhamú, B., López-Rodríguez, M. L. New Serotonin 5-HT1A Receptor Agonists Endowed with Antinociceptive Activity in Vivo. J. Med. Chem. 2013, 56 (20), 7851-7861
NO Ministerio de Economía, Comercio y Empresa
NO Universidad Complutense de Madrid
NO Comunidad de Madrid
DS Docta Complutense
RD 6 abr 2025