Beta-3 Receptor Agonists

Erasmus Bachus, Piotr Ponikowski

Abstract


Beta-3 adrenergic receptors (β3-AR) have a more widespread tissue distribution in the human body as compared to beta1- and beta2 (β1/2)-adrenergic receptors, including in the bladder, brain, adipose tissue and cardiovascular system. Thus, β3- AR are potential drug targets for a wide range of therapeutic areas, both cardiovascular and non-cardiovascular including overactive bladder (OAB), depression, metabolic syndrome, obesity and heart failure (HF).  β3-AR agonists that are selective to the β3-AR include CL 316,243, amibegron (SR58611A), mirabegron (YM-178) and vibegron (RVT-901). However, in HF, study results regarding a possible inotropic effect of β3-AR agonists remain equivocal and some authors report a negative inotropic effect in HF and β3-AR antagonists are also under study.


Keywords


Heart Failure; Beta-3 receptor agonists

Full Text:

Bachus-615

References


Lorca M, Morales-Verdejo C, Vásquez-Velásquez D, Andrades-Lagos J, Campanini- Salinas J, Soto-Delgado J, Recabarren-Gajardo G, Mella J. Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol- Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles. Molecules. 2018 May 16;23(5).

Lönnqvist F, Krief S, Strosberg AD, Nyberg S, Emorine LJ, Arner P. Evidence for a functional beta 3-adrenoceptor in man. Br J Pharmacol. 1993 Nov;110(3):929-36.

Langin D, Portillo MP, Saulnier-Blache JS, Lafontan M. Coexistence of three beta- adrenoceptor subtypes in white fat cells of various mammalian species. Eur J Pharmacol. 1991 Jul 9;199(3):291-301.

Zaagsma J, Nahorski SR. Is the adipocyte beta-adrenoceptor a prototype for the recently cloned atypical ‘beta 3-adrenoceptor’? Trends Pharmacol Sci. 1990 Jan;11(1):3-7.

Widén E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 1995 Aug 10;333(6):348-51.

Arner P. The beta 3-adrenergic receptor - a cause and cure of obesity? N Engl J Med. 1995 Aug 10;333(6):382-3.

Bhadada SV, Patel BM, Mehta AA, Goyal RK. β(3) Receptors: Role in Cardiometabolic Disorders. Ther Adv Endocrinol Metab. 2011 Apr;2(2):65-79.

Shen YT, Zhang H, Vatner SF. Peripheral vascular effects of beta-3 adrenergic receptor stimulation in conscious dogs. J Pharmacol Exp Ther. 1994 Jan;268(1):466-73.

Berlan M, Galitzky J, Bousquet-Melou A, Lafontan M, Montastruc JL. Beta-3 adrenoceptor- mediated increase in cutaneous blood flow in the dog. J Pharmacol Exp Ther. 1994 Mar;268(3):1444-51.

Mohell N, Dicker A. The beta-adrenergic radioligand [3H]CGP-12177, generally classifie as an antagonist, is a thermogenic agonist in brown adipose tissue. Biochem J. 1989 Jul 15;261(2):401-5.

Engel G, Hoyer D, Berthold R, Wagner H. (+/-)[125Iodo] cyanopindolol, a new ligand for beta-adrenoceptors: identification and quantitation of subclasses of beta-adrenoceptors in guinea pig. Naunyn Schmiedebergs Arch Pharmacol. 1981;317(4):277-85.

Tesfamariam B, Allen GT. Beta 1- and beta 2-adrenoceptor antagonist activities of ICI- 215001, a putative beta 3-adrenoceptor agonist. Br J Pharmacol. 1994 May;112(1):55- 8.

Trochu JN, Leblais V, Rautureau Y, Bévérelli F, Le Marec H, Berdeaux A, Gauthier C. Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta. Br J Pharmacol. 1999 Sep;128(1):69-76.

Tagaya E, Tamaoki J, Takemura H, Isono K, Nagai A. Atypical adrenoceptor-mediated relaxation of canine pulmonary artery through a cyclic adenosine monophosphate- dependent pathway. Lung. 1999;177(5):321-32.

Viard P, Macrez N, Coussin F, Morel JL, Mironneau J. Beta-3 adrenergic stimulation of L-type Ca(2+) channels in rat portal vein myocytes. Br J Pharmacol. 2000 Apr;129(7):1497-505.

Atef N, Lafontan M, Doublé A, Hélary C, Ktorza A, Pénicaud L. A specific beta 3-adrenoceptor agonist induces increased pancreatic islet blood flow and insulin secretion in rats. Eur J Pharmacol. 1996 Mar 18;298(3):287-92.

Dessy C, Moniotte S, Ghisdal P, Havaux X, Noirhomme P, Balligand JL. Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization. Circulation. 2004 Aug 24;110(8):948-54.

Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C, Balligand JL. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation. 2001 Mar 27;103(12):1649-55.

Gauthier, C., Leblais, V., Kobzik, L., Trochu, J.N., Khandoudi, N., Bril, A. et al. (1998) The negative inotropic effect of b3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 102: 1377 1384.

Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmacol Ther. 1993 Dec;60(3):405-30.

Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, Cheng CP. Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium. Circ Res. 2001 Sep 28;89(7):599-606.

Zhang ZS, Cheng HJ, Onishi K, Ohte N, Wannenburg T, Cheng CP. Enhanced inhibition of L-type Ca2+ current by beta3-adrenergic stimulation in failing rat heart. J Pharmacol Exp Ther. 2005 Dec;315(3):1203-11.

Strosberg AD. Structure, function, and regulation of adrenergic receptors. Protein Sci. 1993 Aug;2(8):1198-209.

Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional beta3- adrenoceptor in the human heart. J Clin Invest. 1996 Jul 15;98(2):556-62.

Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665-9.

Kong YH, Li WM, Tian Y. [Effect of beta3-adrenoreceptors agonist on beta3- adrenoreceptors expression and myocyte apoptosis in a rat model of heart failure]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2004 Mar;16(3):142-7.

Rasmussen HH, Figtree GA, Krum H, Bundgaard H. The use of beta3-adrenergic receptor agonists in the treatment of heart failure. Curr Opin Investig Drugs. 2009 Sep;10(9):955-62.

Morimoto A, Hasegawa H, Cheng HJ, Little WC, Cheng CP. Endogenous beta3- adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure. Am J Physiol Heart Circ Physiol 2004;286:H2425–H2433.

Donckier JE, Massart PE, Van Mechelen H, Heyndrickx GR, Gauthier C, Balligand JL. Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension. Eur J Clin Invest 2001;31:681 – 689.

Bundgaard H, Liu CC, Garcia A, Hamilton EJ, Huang Y, Chia KK, Hunyor SN, Figtree GA, Rasmussen HH. beta(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification. Circulation 2 10;122: 2699 – 2708.

Kong YH, Zhang Y, Li N, Zhang L, Gao YH, Xue HJ, Li Y, Li WM. [Association between beta3-adrenergic receptor and oxidative stress in chronic heart failure rats]. Zhonghua Xin Xue Guan Bing Za Zhi. 2010 May;38(5):435-9.

Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, Rockman HA. Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation. 2001 Nov 13;104(20):2485-91.

Dinçer UD, Bidasee KR, Güner S, Tay A, Ozçelikay AT, Altan VM. The effect of diabetes on expression of beta1-, beta2-, and beta3-adrenoreceptors in rat hearts. Diabetes. 2001 Feb;50(2):455-61.

Zhou S, Tan AY, Paz O, Ogawa M, Chou CC, Hayashi H, Nihei M, Fishbein MC, Chen LS, Lin SF, Chen PS. Antiarrhythmic effects of beta3-adrenergic receptor stimulation in a canine model of ventricular tachycardia. Heart Rhythm. 2008 Feb;5(2):289-97.

Tagaya E, Tamaoki J, Takemura H, Isono K, Nagai A. Atypical adrenoceptor-mediated relaxation of canine pulmonary artery through a cyclic adenosine monophosphate- dependent pathway. Lung 1999;177:321 – 332.

Dumas M, Dumas JP, Bardou M, Rochette L, Advenier C, Giudicelli JF. Influence of beta- adrenoceptor agonists on the pulmonary circulation. Effects of a beta3-adrenoceptor antagonist, SR 59230A. Eur J Pharmacol 1998;348:223–228.

García-Álvarez A, Pereda D, García-Lunar I, et al. Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension. Basic Res Cardiol. 2016 Jul;111(4):49.

Mitidieri E, Tramontano T, Gurgone D, Imbimbo C, Mirone V, Fusco F, Cirino G, d’Emmanuele di Villa Bianca R, Sorrentino R. β(3) adrenergic receptor activation relaxes human corpus cavernosum and penile artery through a hydrogen sulfide cGMP-dependent mechanism. Pharmacol Res. 2017 Oct;124:100-104.

Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, Markl A, Pouleur AC, Bertrand L, Esfahani H et al. Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 2014;129:451–462.

Balligand JL. Cardiac salvage by tweaking with beta-3-adrenergic receptors. Cardiovasc Res. 2016 Jul 15;111(2):128-33.

Niu X, Watts VL, Cingolani OH, Sivakumaran V, Leyton-Mange JS, Ellis CL, Miller KL, Vandegaer K, Bedja D, Gabrielson KL, Paolocci N, Kass DA, Barouch LA. Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase. J Am Coll Cardiol 2012;59:1979–1987.

Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac endothelium- myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 2015;36:2050–2060.

Cernecka H, Sand C, Michel MC. The odd sibling: features of β3-adrenoceptor pharmacology. Mol Pharmacol. 2014 Nov;86(5):479-84.

Bundgaard H, Axelsson A, Hartvig Thomsen J, Sørgaard M, Kofoed KF, Hasselbalch R, Fry NA, Valeur N, Boesgaard S, Gustafsson F, Køber L, Iversen K, Rasmussen HH. The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur J Heart Fail. 2017 Apr;19(4):566-575.

Balligand JL. Cardiac beta3-adrenergic receptors in the clinical arena: the end of the beginning. Eur J Heart Fail. 2017 Apr;19(4):576-578.

Pouleur AC, Anker S, Brito D, Brosteanu O, Hasenclever D, Casadei B, Edelmann F, Filippatos G, Gruson D, Ikonomidis I, Lhommel R, Mahmod M, Neubauer S, Persu A, Gerber BL, Piechnik S, Pieske B, Pieske-Kraigher E, Pinto F, Ponikowski P, Senni M, Trochu JN, Van Overstraeten N, Wachter R, Balligand JL. Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Beta3-LVH). ESC Heart Fail. 2018 Oct;5(5):830-841.

Shewan LG, Coats AJS, Henein MY. Authors’ Responsibilities and Ethical Publishing. International Cardiovascular Forum Journal 2018;13:3-4, DOI: 10.17987/icfj.v13i0.525




DOI: https://doi.org/10.17987/icfj.v18i0.615

Copyright (c) 2019 The author(s)

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.