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)

We define the pharmacological and pharmacokinetic profiles of a novel α2C-adrenoceptor agonist termed Compound A. This compound has high affinity (Ki) for the human α2C-adrenoceptor (Ki = 12 nM), and 190 - 260 fold selectivity over the α2A- and α2B-adrenoceptor subtypes. In cell based functional assays, Compound A produced good agonist (EC50 = 166 nM) and efficacy (Emax = 64%) responses at the α2C-adrenoceptor, much lower potency and efficacy at the α2A- (EC50 = 1525 nM; Emax = 8%) and α2B- (EC50 = 5814 nM; Emax = 21%) adrenoceptor subtypes and low or no affinity and functional activity at the α1A-, α1B- and α1D-adrenoceptor subtypes. In the human saphenous vein, a post-junctional α2C-adrenoceptor bioassay, Compound A functions as a potent agonist (pD2 = 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 only reached 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-gp transporter resulting in very low CNS penetration. In summary, Compound A is a highly selective, orally active and non CNS penetrating α2C-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.