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J Pharmacol Exp Ther ; 337(1): 256-66, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21233198

ABSTRACT

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.


Subject(s)
Adrenergic Agonists/chemistry , Adrenergic Agonists/pharmacology , Methylurea Compounds/chemistry , Methylurea Compounds/pharmacology , Morpholines/chemistry , Morpholines/pharmacology , Motor Activity/drug effects , Nasal Mucosa/drug effects , Receptors, Adrenergic, alpha-2/metabolism , Saphenous Vein/drug effects , Adrenergic Agonists/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Male , Methylurea Compounds/metabolism , Mice , Mice, Inbred C57BL , Morpholines/metabolism , Motor Activity/physiology , Nasal Mucosa/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Proteins/agonists , Recombinant Proteins/metabolism , Saphenous Vein/metabolism , Swine
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