The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [(R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1′-biphenyl]-2-ylcarbamate], an inhaled compound possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM) and hM3 muscarinic receptors (Ki = 1.3 nM) and hβ2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hβ2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hβ1- and hβ3-adrenoceptors, respectively. In a guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MABA mechanisms. GSK-961081 demonstrated greater lung selectivity than the MA tiotropium and the BA salmeterol. These preclinical findings suggest that GSK-961081 has the potential to be an inhaled lung-selective bronchodilator.
See article at J Pharmacol Exp Ther 2014, 351:190–199.
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