Design, synthesis and in vitro evaluation of (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate: a novel salbutamol derivative with high intrinsic efficacy on the β2 adrenoceptor.
We tested a set of boron containing arylethanolamine derivatives on the human and guinea pig β(2) adrenoceptor (β(2)AR) 3-D structures by docking methodology. The compound with the highest affinity based on docking analysis, (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate (boronterol) was synthesized, characterized and tested in guinea pig tracheal rings at basal tone and with histamine-induced contractions. Boronterol was at least eightfold more potent than salbutamol as a smooth muscle relaxant drug (judged by the EC(50) values) and showed a similar maximal relaxant effect as isoproterenol. ICI118,551 showed competitive antagonism on the relaxing effect of boronterol. These results suggest the β(2)AR agonist action of boronterol.
Soriano-Ursúa
Marvin A
MA
Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón 11340, Mexico. msoriano@ipn.mx
Correa-Basurto
José
J
Valencia-Hernández
Ignacio
I
Amezcua-Gutiérrez
Marcos A
MA
Padilla-Martínez
Itzia I
II
Trujillo-Ferrara
José G
JG
D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009465:Neuromuscular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
C555989:(R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate; D058666:Adrenergic beta-2 Receptor Agonists; D009465:Neuromuscular Agents; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol; D000420:Albuterol