Ragusa, GiulioGómez Cañas, MaríaPazos Rodríguez, María RuthFernández Ruiz, José JavierGarcía Arencibia, MoisésMurineddu, Gabriele2024-01-182024-01-182015Ragusa G, Gómez-Cañas M, Morales P, Hurst DP, Deligia F, Pazos R, Pinna GA, Fernández-Ruiz J, Goya P, Reggio PH, Jagerovic N, García-Arencibia M, Murineddu G. Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB2 receptor antagonists. Eur J Med Chem. 2015 Aug 28;101:651-67. doi: 10.1016/j.ejmech.2015.06.0570223-523410.1016/j.ejmech.2015.06.057https://hdl.handle.net/20.500.14352/93748During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4- methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [35S]-GTPgS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model.engjournal articlehttps://doi.org/10.1016/j.ejmech.2015.06.057restricted access577.2BioisosterismCB2 antagonismCannabinoid receptorsDocking studiesSynthesisCiencias Biomédicas24 Ciencias de la Vida