Target Validation Information
TTD ID	T31424
Target Name	Adrenergic receptor Alpha-2 (ADRA2)
Type of Target	Successful
Drug Potency against Target	Clonidine	Drug Info	ED50 = 0.0032~1.0 mg/kg	[1]
	Connexyn	Drug Info	pKi < 6	[3]
	Dexmedetomidine	Drug Info	ED50 = 0.001~0.032 mg/kg	[1]
	Guanabenz	Drug Info	pKi = 6.7	[3]
	Nicergoline	Drug Info	IC50 = 22000 nM	[5]
	Oxymetazoline	Drug Info	Ki = 0.24 nM	[2]
	Tizanidine	Drug Info	pKi = 6.26	[3]
	Yohimbine	Drug Info	pKi = 8.66	[3]
Action against Disease Model	Connexyn	Drug Info	EC50 on C fiber compound action potentials of rat sciatic nerves: 170nM	[6]
	Dexmedetomidine	Drug Info	suppressed the amplitude of delayed rectifier K+ current [IK(DR)] in a concentration-dependent manner in NG108-15 cells IC50: 4600 nM	[4]
	Guanabenz	Drug Info	Guanabenz (E-2,6-dichlorobenzylideneaminoguanidine acetate, Wy-8678) and its identified metabolites were tested for their ability to displace clonidine from the cerebral |?2-receptors of rat and dog. The Kj's for inhibition of clonidine binding to rat membranes were 1.97, 0.96, 14.0, and 108 nM for clonidine, guanabenz, p-hydroxyguanabenz, and the Z-isomer of guanabenz, respectively. The other metabolites at concentrations of 10,000 nM did not displace clonidine. Scatchard analysis indicated single populations of binding sites with KD' s of 2.37 and 2.39 nM and Bmax's of5.39 and 5.12 pmol/g for rat and dog preparations, respectively. Hill analysis yielded coefficients approximating unity, indicating a lack of cooperativity in binding. The high affinity of guanabenz relative to that of its metabolites for the |?2-receptor provided the basis for the development of an assay capable of discriminating guanabenz from its weakly hypotensive (p-hydroxyguanabenz and the Z-isomer of guanabenz) and pharmacologically inactive (2-6, dichlorobenzyl alcohol,2,6-dichlorobenzaldehyde, 2,6-dichlorobenzaldehyde azine, 2,6-dichlorobenzaldehyde semicarbizone, creatinine adduct of 2,6-dichlorobenzaldehyde, and an isomer of the creatinine adduct) metabolites. Antihypertensive agents with different mechanisms of action such as indoramin, prazosin, debrisoquine, and bethanidine bound little, if at all, and thus will not interfere with the assay of guanabenz.
	Oxymetazoline	Drug Info	concentration-related increases in tension of the rat isolated aorta preparation when the drug concentration was increased c uMulatively in the organ bath EC50: 770 nM
References
REF 1	Alpha2-adrenergic receptor agonists as analgesics. Curr Top Med Chem. 2001 Aug;1(3):193-7.
REF 2	Recent advances in 5-HT1B/1D receptor antagonists and agonists and their potential therapeutic applications. Curr Top Med Chem. 2002 Jun;2(6):559-74.
REF 3	Agonists and antagonists targeting the different alpha2-adrenoceptor subtypes. Curr Top Med Chem. 2007;7(2):163-86.
REF 4	Dexmedetomidine, an alpha2-adrenergic agonist, inhibits neuronal delayed-rectifier potassium current and sodium current. Br J Anaesth. 2009 Aug;103(2):244-54.
REF 5	Hemoglobin Raleigh (beta1 valine replaced by acetylalanine). Structural and functional characterization. Biochemistry. 1977 Nov 1;16(22):4872-9.
REF 6	The alpha 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg. 1993 Feb;76(2):295-301.

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