title: Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a beta2 adrenoceptor agonist.
abstract: In this study, 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, (BR-AEA), was designed, synthesized, characterized and tested in docking studies and in vitro. Previous to its synthesis, a set of compounds, including well-known ligands and boron containing compounds, were studied under docking simulations. BR-AEA showed greater affinity than these well-known agonists and was found to be slightly closer than salbutamol to the residues in the TM5 and TM3 of the beta(2) adrenoceptor (beta(2)AR), making a greater number of interactions with them, including some that are apparently key to greater affinity and beta(2)AR activation. This study suggests that affinity is closely related to the interactions of the boron atom, as well as the capacity of boronic acid moieties to make a network of hydrogen bonds with the beta(2)AR. In vitro, the relaxing effects of BR-AEA on isolated guinea pig tracheal rings were compared with salbutamol. The EC(50) values for BR-AEA were at least five-fold lower than for salbutamol, showing the greater potency of the former. Additionally, propranolol and ICI 118,551 showed competitive antagonism in relation to the relaxing effect of the test compound (pA(2) 6.204+/-0.367 and 9.089+/-0.470, respectively).
authors.affiliation: Departamento de Bioquímica, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, DF México, Mexico.
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Soriano-Ursúa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Valencia-Hernández
authors.forename: Mónica G
authors.initials: MG
authors.lastname: Arellano-Mendoza
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.forename: José G
authors.initials: JG
authors.lastname: Trujillo-Ferrara
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol / Q000031:analogs & derivatives; D000818:Animals; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002082:Butylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019295:Computational Biology; D015195:Drug Design; D000431:Ethanol / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: C542224:1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo(4.4.0)deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol; D058666:Adrenergic beta-2 Receptor Agonists; D001643:Bridged Bicyclo Compounds; D002082:Butylamines; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D000431:Ethanol; D000420:Albuterol