Target Validation Information
Target ID T44068
Target Name Beta-1 adrenergic receptor
Target Type
Successful
Drug Potency against Target Propranolol Drug Info IC50 = 100 nM/L [553199]
Pindolol Drug Info IC50 = 100 nM [552638]
1-(2-isopropylphenoxy)-3-morpholinopropan-2-ol Drug Info Ki = 12 nM [530883]
Bisoprolol Drug Info Ki = 15 nM [552672]
(+/-)-nantenine Drug Info Ki = 8565 nM [530558]
Norepinephrine Drug Info pKi = 6.71 [552671]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [531079]
Oxprenolol Drug Info IC50 = 19 ng/mL [553118]
Epinephrine Drug Info pKi = 6.67 [552671]
1-(1H-Indol-4-yloxy)-3-phenethylamino-propan-2-ol Drug Info Ki = 4 nM [533374]
Atenolol Drug Info Ki = 219 nM [552672]
CGP-12177A Drug Info Ki = 0.25 nM [526033]
Nebivolol Drug Info IC50 = 22 nM [553119]
(R,S)-(-)-fenoterol Drug Info Ki = 18900 nM [528842]
(R,R)-(-)-fenoterol Drug Info Ki = 14800 nM [528842]
Betaxolol Drug Info Ki = 6.2 nM [552672]
Isoproterenol Drug Info Ka = 340 nM [553158]
1-(2-allylphenoxy)-3-morpholinopropan-2-ol Drug Info Ki = 114 nM [530883]
L-755507 Drug Info Ki = 570 nM [526033]
Metipranolol Drug Info IC50 = 6900 nM [552361]
DICHLOROISOPROTERENOL Drug Info Ki = 51 nM [533801]
L-796568 Drug Info IC50 = 2300 nM [530748]
Action against Disease Model Levobetaxolol 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. [535957] Drug Info
Ritodrine inhibited the amplitude and frequency of rat uterine contraction IC50: 470 nM [535115] Drug Info
Sotalol Anti-aggregatory activity in h uMan platelet rich plasma (PRP) IC50: 500000 nM [553270] Drug Info
Esmolol 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 [553023] Drug Info
Alprenolol 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. [553258] Drug Info
References
Ref 553199Pharmacological 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 535957Binding 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 535115Tocolytic effects of a long-acting beta2-adrenoceptor agonist, formoterol, in rats. J Pharm Pharmacol. 2000 Nov;52(11):1417-23.
Ref 552638Characterization of beta-adrenoreceptors on smooth muscle cells from guinea pig stomach. Am J Physiol. 1990 Sep;259(3 Pt 1):G436-42.
Ref 530883Bioorg Med Chem Lett. 2010 Jun 1;20(11):3399-404. Epub 2010 Apr 9.A vHTS approach for the identification of beta-adrenoceptor ligands.
Ref 552672Recent advances in identification and characterization of beta-adrenoceptor agonists and antagonists. Curr Top Med Chem. 2007;7(2):207-16.
Ref 553270Thrombolytic activity of beta-adrenolytic drug, sotalol. J Physiol Pharmacol. 1998 Mar;49(1):51-60.
Ref 530558Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.
Ref 552671Agonists and antagonists targeting the different alpha2-adrenoceptor subtypes. Curr Top Med Chem. 2007;7(2):163-86.
Ref 531079J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Ref 553118A 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 552671Agonists and antagonists targeting the different alpha2-adrenoceptor subtypes. Curr Top Med Chem. 2007;7(2):163-86.
Ref 533374J Med Chem. 1986 Aug;29(8):1524-7.Synthesis and beta-adrenergic receptor blocking potency of 1-(substituted amino)-3-(4-indolyloxy)propan-2-ols.
Ref 552672Recent advances in identification and characterization of beta-adrenoceptor agonists and antagonists. Curr Top Med Chem. 2007;7(2):207-16.
Ref 526033J Med Chem. 2001 Apr 26;44(9):1456-66.(4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists.
Ref 553119Beta-adrenoceptor-mediated cAMP accumulation in cardiac cells: effects of nebivolol. Eur J Pharmacol. 1989 Dec 5;172(6):471-9.
Ref 528842J Med Chem. 2007 Jun 14;50(12):2903-15. Epub 2007 May 17.Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor.
Ref 528842J Med Chem. 2007 Jun 14;50(12):2903-15. Epub 2007 May 17.Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor.
Ref 552672Recent advances in identification and characterization of beta-adrenoceptor agonists and antagonists. Curr Top Med Chem. 2007;7(2):207-16.
Ref 553158Human ciliary process adrenergic receptor: pharmacological characterization. Invest Ophthalmol Vis Sci. 1981 Dec;21(6):798-804.
Ref 553023Esmolol cardioplegia: the cellular mechanism of diastolic arrest. Cardiovasc Res. 2010 Aug 1;87(3):552-60. doi: 10.1093/cvr/cvq058. Epub 2010 Feb 22.
Ref 530883Bioorg Med Chem Lett. 2010 Jun 1;20(11):3399-404. Epub 2010 Apr 9.A vHTS approach for the identification of beta-adrenoceptor ligands.
Ref 526033J Med Chem. 2001 Apr 26;44(9):1456-66.(4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists.
Ref 552361Metipranolol attenuates lipid peroxidation in rat brain: a comparative study with other antiglaucoma drugs. Graefes Arch Clin Exp Ophthalmol. 2003 Oct;241(10):827-33. Epub 2003 Jul 29.
Ref 533801J Med Chem. 1994 May 13;37(10):1518-25.The [(methyloxy)imino]methyl moiety as a bioisoster of aryl. A novel class of completely aliphatic beta-adrenergic receptor antagonists.
Ref 530748Bioorg Med Chem Lett. 2010 Mar 15;20(6):1895-9. Epub 2010 Feb 4.Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.
Ref 553258Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity. J Biol Chem. 1997 Nov 14;272(46):28849-52.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.