Target Validation Information
TTD ID T44068
Target Name Adrenergic receptor beta-1 (ADRB1)
Type of Target
Successful
Drug Potency against Target Atenolol Drug Info Ki = 219 nM [14]
Betaxolol Drug Info Ki = 6.2 nM [14]
Bisoprolol Drug Info Ki = 15 nM [14]
Epinephrine Drug Info pKi = 6.67 [13]
Isoproterenol Drug Info Ka = 340 nM [18]
Metipranolol Drug Info IC50 = 6900 nM [11]
Nebivolol Drug Info IC50 = 22 nM [17]
Norepinephrine Drug Info pKi = 6.71 [13]
Oxprenolol Drug Info IC50 = 19 ng/mL [16]
Pindolol Drug Info IC50 = 100 nM [12]
Propranolol Drug Info IC50 = 100 nM/L [19]
(+/-)-nantenine Drug Info Ki = 8565 nM [3]
(R,R)-(-)-fenoterol Drug Info Ki = 14800 nM [2]
(R,S)-(-)-fenoterol Drug Info Ki = 18900 nM [2]
1-(1H-Indol-4-yloxy)-3-phenethylamino-propan-2-ol Drug Info Ki = 4 nM [7]
1-(2-allylphenoxy)-3-morpholinopropan-2-ol Drug Info Ki = 114 nM [5]
1-(2-isopropylphenoxy)-3-morpholinopropan-2-ol Drug Info Ki = 12 nM [5]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [6]
Dichloroisoproterenol Drug Info Ki = 51 nM [8]
L-755507 Drug Info Ki = 570 nM [1]
L-796568 Drug Info IC50 = 2300 nM [4]
[3H]CGP12177 Drug Info Ki = 0.25 nM [1]
Action against Disease Model Alprenolol Drug Info The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon. Signal transduction by n uMerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta2-adrenergic receptor (beta2AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin. The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction. Here we report that complexes of beta2AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta2AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins. The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors. Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization. [20]
Esmolol Drug Info Contraction, expressed as sarcomere shortening (SS), was calculated as the difference between the systolic and the diastolic SL. IC50 for contraction: 160 000 nM/L [15]
Levobetaxolol Drug Info The current study determined the relative affinities and selectivities of n uMerous beta-adrenoceptor antagonists at the endogenous beta(1)- and beta(2)-adrenoceptors in guinea pig heart and lung, respectively, using [(3)H]-CGP12177. Specific binding of [(3)H]-CGP12177 comprised 80 +/- 0.2% (n = 11) and 94 +/- 0.2% (n = 16) of the total binding in washed heart and lung homogenates, respectively. Concentration-dependent displacement of [(3)H]-CGP12177 binding from beta-adrenoceptors in both preparations was observed with nine different beta-adrenoceptor antagonists. Levobetaxolol, betaxolol, CGP-20712A, levobunolol, and timolol yielded bi-phasic (two-site-fit) competition curves in the heart, while CGP-20712A, ICI-118551 and levobunolol produced bi-phasic curves in the lung preparation. The high-affinity component of [(3)H]-CGP12177 binding in the heart and lung reflected binding to beta(1)-receptors and beta(2)-receptors, respectively. The binding inhibition parameters (IC(50)s) for displacement of [(3)H]-CGP12177 from these predominantly high-affinity sites were: levobetaxolol (24.9 +/- 1.6 nM heart, 4810 +/- 367 nM lung), racemic betaxolol (37.9 +/- 8.7 mM heart; 8840 +/- 424 mM lung), CGP-20712A (4.6 +/- 0.9 nM heart; 171,000 +/- 109,000 nM lung), ICI-118551 (9230 +/- 3240 nM heart; 2.9 +/- 0.6 nM lung), levobunolol (42 +/- 15 nM heart, 0.3 +/- 0.2 nM lung), (l)-timolol (3.1 nM heart, 2.9 +/- 1.5 nM lung), ICI-215001 (5840 +/- 114 nM heart; 26100 +/- 3200 nM lung), BRL-37344 (83,300 +/- 2660 nM heart; 13,200 +/- 1250 lung). These data indicated that while levobetaxolol and betaxolol possessed a 193-233-fold selectivity for beta(1)-receptors, levobunolol exhibited a 140-fold beta(2)-receptor selectivity and (l)-timolol was essentially nonselective. [10]
Ritodrine Drug Info inhibited the amplitude and frequency of rat uterine contraction IC50: 470 nM [9]
Sotalol Drug Info Anti-aggregatory activity in h uMan platelet rich plasma (PRP) IC50: 500000 nM [21]
References
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REF 9 Tocolytic effects of a long-acting beta2-adrenoceptor agonist, formoterol, in rats. J Pharm Pharmacol. 2000 Nov;52(11):1417-23.
REF 10 Binding affinities of ocular hypotensive beta-blockers levobetaxolol, levobunolol, and timolol at endogenous guinea pig beta-adrenoceptors. J Ocul Pharmacol Ther. 2004 Apr;20(2):93-9.
REF 11 Metipranolol attenuates lipid peroxidation in rat brain: a comparative study with other antiglaucoma drugs. Graefes Arch Clin Exp Ophthalmol. 2003 Oct;241(10):827-33.
REF 12 Characterization of beta-adrenoreceptors on smooth muscle cells from guinea pig stomach. Am J Physiol. 1990 Sep;259(3 Pt 1):G436-42.
REF 13 Agonists and antagonists targeting the different alpha2-adrenoceptor subtypes. Curr Top Med Chem. 2007;7(2):163-86.
REF 14 Recent advances in identification and characterization of beta-adrenoceptor agonists and antagonists. Curr Top Med Chem. 2007;7(2):207-16.
REF 15 Esmolol cardioplegia: the cellular mechanism of diastolic arrest. Cardiovasc Res. 2010 Aug 1;87(3):552-60.
REF 16 A nonsteady-state agonist antagonist interaction model using plasma potassium concentrations to quantify the beta-2 selectivity of beta blockers. J Pharmacol Exp Ther. 1989 Apr;249(1):297-302.
REF 17 Beta-adrenoceptor-mediated cAMP accumulation in cardiac cells: effects of nebivolol. Eur J Pharmacol. 1989 Dec 5;172(6):471-9.
REF 18 Human ciliary process adrenergic receptor: pharmacological characterization. Invest Ophthalmol Vis Sci. 1981 Dec;21(6):798-804.
REF 19 Pharmacological actions of the selective and non-selective beta-adrenoceptor antagonists celiprolol, bisoprolol and propranolol on human bronchi. Br J Pharmacol. 1994 Nov;113(3):1043-9.
REF 20 Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity. J Biol Chem. 1997 Nov 14;272(46):28849-52.
REF 21 Thrombolytic activity of beta-adrenolytic drug, sotalol. J Physiol Pharmacol. 1998 Mar;49(1):51-60.

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