NS-49, a novel α1a-adrenoceptor-selective agonist characterization using recombinant human α1-adrenoceptors

α₁-Adrenoceptors comprise a heterogeneous family and subtype-selective ligands are valuable in studying the functional role of each receptor subtype. Using the Chinese hamster ovary (CHO) cells stably expressing the cloned human α₁-adrenoceptor subtypes (α_1a, α_1b, and α_1d)¹, we have compared a newly synthesized phenethylamine class agonist (R)-(−)-3′-(2-amino-1-hydroxythyl)-4′- fluoromethanesulfonanilide hydrochloride (NS-49) with imidazoline class agonist oxymetazoline in their binding affinities and intrinsic activities in causing transient increases of cytosolic Ca²⁺ concentrations ([Ca²⁺]₁ response). Radioligand binding sites with 2-[β-(4-hydroxy-3-[¹²⁵I]iodophenyl)ethylamino-methyl]tetralone ([¹²⁵I]HEAT) showed NS-49 and oxymetazoline had higher affinities at α_1a- than at α_1b- and α_1d-subtypes (−log K_i values at α_1a−, α_1b− and α_1d-subtype: 6.18, 5.13, and 5.38 for NS-49; 8.19, 6.50, and 6.44 for oxymetazoline, respectively). In functional studies, both oxymetazoline and NS-49 worked as a selective and partial agonist at α_1a-subtype; however, NS-49 is more efficacious than oxymetazoline. NS-49 is the phenethylamine class of α₁-adrenoceptor partial agonist relatively selective and efficacious for the human α_1a-adrenoceptor subtype. NS-49 would be potentially useful for studying the physiological role of α₁-adrenoceptor subtype.