Background:

ARC 239 dihydrochloride is a selective antagonist of α2B adrenoceptor with pKD value of 8.8 [1].

α2B adrenoceptor is a G-protein coupled receptor. α2-adrenergic receptors include three subtypes: α2A, α2B and α2C, which play an important role in regulating neurotransmitter release from adrenergic neurons in the central nervous system and from sympathetic nerves.

ARC 239 dihydrochloride is a selective α2B adrenoceptor antagonist. In rat brain, ARC 239 inhibited the binding of 5-HTIA receptor radioligands 8-OH-DPAT and RX 821002 to cortical membranes with Ki values of 63.1 and 136 nM respectively, which suggested that ARC 239 recognized 5-HT1A receptor [2]. Treatment human platelets with ARC 239 significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), epinephrine and arachidonic acid and increased collagen/epinephrine closure time, which suggested that α2B adrenoceptor play a critical role in platelet aggregation [3]. In cervical samples isolated from pregnant rats, ARC 239 effectively inhibited noradrenaline-stimulated contractions [4].

In C57BL/6 mice with gastric mucosal damage induced by acidified ethanol, ARC 239 (10.4 nM) antagonized gastroprotective effect induced by α2-adrenoceptor agonists [5].

参考文献:
[1].  Bylund DB, Ray-Prenger C, Murphy TJ. Alpha-2A and alpha-2B adrenergic receptor subtypes: antagonist binding in tissues and cell lines containing only one subtype. J Pharmacol Exp Ther, 1988, 245(2): 600-607.
[2].  Meana JJ, Callado LF, Pazos A, et al. The subtype-selective alpha 2-adrenoceptor antagonists BRL 44408 and ARC 239 also recognize 5-HT1A receptors in the rat brain. Eur J Pharmacol, 1996, 312(3): 385-388.
[3].  Marketou ME, Kintsurashvili E, Androulakis NE, et al. Blockade of platelet alpha2B-adrenergic receptors: a novel antiaggregant mechanism. Int J Cardiol, 2013, 168(3): 2561-2566.
[4].  Gál A, Kolarovszki-Sipiczki Z, et al. The effect of the ARC 239 on the myometrial and cervical action in the rat, in vitro. Acta Pharm Hung, 2009, 79(2): 75-80.
[5].  Zádori ZS, Shujaa N, Brancati SB, et al. Both α2B- and α2C-adrenoceptor subtypes are involved in the mediation of centrally induced gastroprotection in mice. Eur J Pharmacol, 2011, 669(1-3): 115-120.