Design, Synthesis, Binding and Docking-Based 3D-QSAR Studies of 2-Pyridylbenzimidazoles—A New Family of High Affinity CB1 Cannabinoid Ligands

Molecules

Jaime A. Mella-Raipán¹  Carlos F. Lagos³  Gonzalo Recabarren-Gajardo³  Christian Espinosa-Bustos³  Javier Romero-Parra³  Hernán Pessoa-Mahana²  Patricio Iturriaga-Vásquez⁴ 

[1] Departamento de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Casilla 5030, Avda. Gran Bretaña 1111, Playa Ancha, Valparaíso, Chile;Departamento de Química Orgánica y Físicoquímica, Facultad de Química y Ciencias Farmacéuticas, Universidad de Chile, Casilla 233, Santiago, Chile;Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, 22, Santiago, Chile;Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 233, Santiago, Chile

关键词: cannabinoid;    CB1 receptor;    binding;    docking;    3D-QSAR;   

DOI  :  10.3390/molecules18043972

来源: mdpi

【 摘 要 】

A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with K_i values in the nanomolar range. JM-39 (compound 39) was the most active of the series (K_iCB1 = 0.53 nM), while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q² = 0.710, r² = 0.998, r²_pred = 0.823).

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.