NS-49, a novel alpha(1a)-adrenoceptor-selective agonist characterization using recombinant human alpha(1)-adrenoceptors

alpha(1)-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 alpha(1)-adrenoceptor subtypes (alpha(1a), a(1b), and alpha(1d))(1), we have compared a newly synthesized phenethylamine class agonist (R)-(-)-3'-(2-amino-1-hydroxyethyl)-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+](i) response). Radioligand binding studies with 2-[beta-(4-hydroxy-3-[I-125]iodophenyl)ethylamino-methyl]tetralone ([I-125]HEAT) showed NS-49 and oxymetazoline had higher affinities at alpha(1a)- than at alpha(1b)- and alpha(1d)-subtypes(-log K-i values at alpha(1a)-, alpha(1b)- and alpha(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 alpha(1a)-subtype; however, NS-49 is more efficacious than oxymetazoline. NS-49 is the phenethylamine class of alpha(1)-adrenoceptor partial agonist relatively selective and efficacious for the human alpha(1a)-adrenoceptor subtype. NS-49 would be potentially useful for studying the physiological role of alpha(1)-adrenoceptor subtype.