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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).
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2011 Apr; Vol. 337 (1), pp. 256-66. Date of Electronic Publication: 2011 Jan 13. - Publication Year :
- 2011
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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.
- Subjects :
- 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
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
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 337
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 21233198
- Full Text :
- https://doi.org/10.1124/jpet.110.175794