Pharmacological Characterization of a Novel alpha(2C)-Adrenoceptor Agonist N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N '-methylurea (Compound A)

[摘要]：We define the pharmacological and pharmacokinetic profiles of a novel alpha(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 alpha(2C)-adrenoceptor (K-i = 12 nM), and 190- to 260-fold selectivity over the alpha(2A)- and alpha(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC50 = 166 nM) and efficacy (E-max = 64%) responses at the alpha(2C)-adrenoceptor, much lower potency and efficacy at the alpha(2A)-adrenoceptor (EC50 = 1525 nM; E-max = 8%) and alpha(2B)-adrenoceptor (EC50 = 5814 nM; E-max = 21%) subtypes, and low or no affinity and functional activity at the alpha(1A)-, alpha(1B)-, and alpha(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional alpha(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 (EC50 = 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 alpha(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.

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