Pharmacological characterization of a novel α2C-adrenoceptor agonist N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N'-methylurea (compound A)

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 337; no. 1; pp. 256 - 266
• Main Authors: Corboz, Michel R, Rivelli, Maria A, McCormick, Kevin D, Wan, Yuntao, Shah, Himanshu, Umland, Shelby, Lieber, Gisela, Jia, Yanlin, McLeod, Robbie L, Morgan, Cynthia, Varty, Geoffrey B, Wu, Jie, Feng, Kung-I, Boyce, Christopher W, Aslanian, Robert G, Palamanda, Jai, Nomeir, Amin A, Korfmacher, Walter, Hunter, John C, Anthes, John C, Hey, John A
• Format: Journal Article
• Language: English
• Published: United States 01.04.2011
• Subjects: Adrenergic Agonists - chemistry; Adrenergic Agonists - metabolism; Adrenergic Agonists - pharmacology; Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Male; Methylurea Compounds - chemistry; Methylurea Compounds - metabolism; Methylurea Compounds - pharmacology; Mice; Mice, Inbred C57BL; Morpholines - chemistry; Morpholines - metabolism; Morpholines - pharmacology; Motor Activity - drug effects; Motor Activity - physiology; Nasal Mucosa - drug effects; Nasal Mucosa - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2 - metabolism; Recombinant Proteins - agonists; Recombinant Proteins - metabolism; Saphenous Vein - drug effects; Saphenous Vein - metabolism; Swine
• DOI: 10.1124/jpet.110.175794

We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.