2026-06-01T18:53:05Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1144212025-03-18T14:13:17Zcom_20.500.14352_14col_20.500.14352_15

Valhondo Falcón, Margarita Marco, Isabel Martín-Fontecha Corrales, María Del Mar Vázquez Villa, María Del Henar Ramos Atance, José Antonio Berkels, Reinhard Lauterbach, Thomas Benhamú Salama, Bellinda López Rodríguez, María Luz 2025-01-15T11:38:37Z 2025-01-15T11:38:37Z 2013-10-24 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 0022-2623 10.1021/jm400766k https://hdl.handle.net/20.500.14352/114421 1520-4804 https://doi.org/10.1021/jm400766k https://pubs.acs.org/doi/10.1021/jm400766k 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. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ restricted access Attribution-NonCommercial-NoDerivatives 4.0 International New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo journal article