title: NS-49, a novel alpha 1a-adrenoceptor-selective agonist characterization using recombinant human alpha 1-adrenoceptors.
abstract: alpha 1-Adrenoreceptors 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, alpha 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-hydroxyl-3-[125I]iodophenyl)ethylamino-methyl]tetralone ([125I]HEAT) showed NS-49 and oxymetazoline had higher affinities at alpha 1a-than at alpha 1b- and alpha 1d-subtypes (-log Ki 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.
authors.affiliation: Department of Molecular, Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Obika
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: K
authors.initials: K
authors.lastname: Horie
authors.forename: R
authors.initials: R
authors.lastname: Foglar
authors.forename: K
authors.initials: K
authors.lastname: Kimura
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D009638:Norepinephrine / Q000494:pharmacology; D010109:Oxymetazoline / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: C092989:3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000813:Anilides; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; D010656:Phenylephrine; D010109:Oxymetazoline; D002118:Calcium; D009638:Norepinephrine