• α- and β-adrenergic receptor selectivity

  • Adrenergic agonists have been developed which exhibit binding and activation preference for one or another adrenergic receptor type.

    • Some agents bind preferably to α-receptors while others exhibit selectivity for β-receptors.

    • For the case of agonists, binding is associated with receptor activation; therefore, binding selectivity for agonists corresponds to activation selectivity also.

    • For antagonists the singular event is binding, given that antagonists cannot activate receptors (here the references to "pure" antagonists).

    • A drug may exhibit receptor selectivity, a non-absolute preference for a particular receptor type. A drug that is described as "highly specific" will be one that exhibit substantial selectivity for the receptor. Classification of α-and β -adrenergic receptors with respect to receptor affinities is described below.³⁵

  • Brief initial comment about some adrenergic agents.

    • Epinephrine a.k.a. adrenaline activates both α- and β-adrenergic receptors. ³⁵

      • Epinephrine

      • The physiological effects actually observed depend in part on dosage. Because the drug activates both adrenergic receptor types, epinephrine at higher doses can cause significant vasoconstriction. Through cardiac β receptor activation, epinephrine mediates positive inotropic (increased myocardial contractility) and positive chronotropic (increased heart rate) cardiac effects.

      • Hypertensive responses to epinephrine can be explained both by increased cardiac output as a result of enhanced contractility and heart rate as well as by increased vascular resistance due to α receptor activation.

      • In a subset of vessels, β₂ receptor activation causes vasodilatation. Skeletal muscle blood vessels respond in this way. Blood pressure effects, then, following epinephrine depend on a balance between α-adrenergic receptor mediated vasoconstriction and β₂ adrenergic receptor mediated vasodilatation. The response to epinephrine may involve both an increase in the systolic pressure (α-adrenergic receptor mediated) along with a decrease in diastolic pressure (reflecting the β₂-adrenergic receptor activation). The net effect may be an increase in mean blood pressure with a widening pulse pressure.

    • Norepinephrine (Levophed) a.k.a. noradrenaline, levarterenol is a principal agonist of both α₁ and α₂ adrenergic receptors but also activates β₁ adrenergic receptors about to the same extent observed with epinephrine.³⁵  

      • Norepinephrine (Levophed)

      • Following norepinephrine infusion, the blood pressure will rise due to prominent α-receptor activation; however, heart rate is likely to decrease, despite norepinephrine activity at β one receptor sites. The reduction in heart rate is explained by an autonomic reflex mediated by baroreceptors (the increased blood pressure causes a parasympathetic (cholinergic)-mediated decrease in heart rate). The cholinergic, parasympathetic response is sufficient to overcome the norepinephrine direct cardiac β₁ action.

       

    • Some agents are described as direct-acting sympathomimetic drugs-direct activators at the receptors.³⁵

      • For example, phenylephrine (Neo-Synephrine) is classified as a nearly pure α₁ agonist. The absence of the catecholamine structure renders phenylephrine unsuitable as a COMT-substrate (the enzyme catechol-o-methyl transferase thus cannot contribute to phenylephrine inactivation); therefore, phenylephrine exhibits an extended duration of action.

      • Phenylepinephrine (Neo-Synephrine)

         

      • A selective α₁ adrenergic agonist, midodrine (Amatine, ProAmatine)  is classified as a prodrug. This designation indicates that the physiological response noted after midodrine administration is due to a metabolite, in this case desglymidodrine. Desglymidrine differs from methoxamine only by lacking a CH₃ (methyl) group on a side chain. (compared 3D structures below)

      • Midodrine may be used clinically to manage orthostatic hypotension secondary to and autonomic dysfunction which impairs blood pressure homeostasis.

      • Mitrodrine (Amatine, ProAmatine)

       

      •  Desglymidodrine

       

    • Methoxamine (Vasoxyl) is another direct acting α₁ receptor agonist that both increases blood pressure (α₁ mediated vasoconstriction) and bradycardia (reduced heart rate, a parasympathetic-mediated autonomic reflex). Parasympathetic reflexes that reduce heart rate as described above are mediated by the vagus nerve.³⁵

      • Methoxamine (Vasoxyl)

         

    • Other drugs exhibit relative α₂ selectivity and act to reduce blood pressure as a result of central nervous system effects³⁵ , perhaps by reducing sympathetic outflow.

      • Agents of this type useful in hypertension management include clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin) , and guanfacine (Intuniv, Tenex) .

        • Clonidine (Catapres)

           

        • Methyldopa (Aldomet)

         

        • Guanabenz (Wytensin)

         

        • Guanfacine (Intuniv, Tenex)

        • Another centrally-acting α₂-selective agonist which appears helpful in sedating patients during initial intubation and subsequent mechanical ventilation is dexmedetomidine (Precedex).

          • Dexmedetomidine (Precedex)

    • Xylometazoline (Otrivin) and oxymetazoline (Afrin), both direct-acting α agonists, are effective topical decongestants which act by constriction of nasal mucosa.³⁵

      • Xylometazonline (Otrivin)

         

      • Oxymetazoline (Afrin)

    • Isoproterenol (Isuprel) a.k.a. isoprenaline is principally an agonist at β receptors, causing increased myocardial contractility and increased heart rate.³⁵

      • Isoproterenol (Isuprel, Medihaler-Iso)

      •  In addition, its β-effects promote vasodilation sufficient to reduce both mean arterial and diastolic blood pressure, although systolic pressure might be either slightly decreased or slightly increased.³⁵

 

• *GU--genitourinary

• ** IP3: Inositol trisphosphate; DAG:  diacylglycerol

   

  • IP₃:DAG Second Messengers

    IP3	DAG

α₂ Receptors^49,46

Receptor type: α2 (includes α2A, α2B, α2D)

example agonist:  clonidine;  α2Aagonist: oxymetazoline

example α2: antagonist:  yohimbine; α2A,α2B:  prazosin

Signal transduction: G protein (Gi ↓ adenylyl cyclase activity); Gi (βγ subunits): ↑K+ channel conductance; Go : ↓Ca2+ channel conductance (L- and N-type) ↓cAMP (true for all α2 receptor subtypes)

Receptor type: α2

Agonist effectiveness:  Epinephrine ≥ Norepinephrine >> Isoproterenol; clonidine (classical α2 agonist)

Tissue Effects following α2-receptor activation Platelets:  aggregation Pancreatic islet β cells:  reduction in insulin release Synaptic endings:  reduction in norepinephrine release Vascular smooth muscle:  contraction

β Receptors^49,46

Receptor type: β (includes β1, β2, β3)

example agonist:  isoproterenol;  β1 agonist: dobutamine; β2 agonist : albuterol

example β: antagonist: propranol;  β1 antagonist: bextaxolol, metaprolol; β2 antagonist: butoxamine

Signal transduction: G protein (Gs) ↑ cAMP (true for all β receptor subtypes),  ↑adenylyl cyclase,↑ L-type Ca2+ channels

Receptor type: β1

Agonist effectiveness:  Isoproterenol > Epinephrine = Norepinephrine; dobutamine (antagonist:  CGP 20712A)

Tissue Effects following β1 -receptor activation Renal:  juxtaglomerular cells:  increased renin secretion Cardiac: increased myocardial contractility (positive inotropism) increased rate of contraction increased AV nodal conduction velocity

Receptor type: β2

Agonist effectiveness:  Isoproterenol > Epinephrine >> Norepinephrine (antagonist ICI 118551); terbutaline (antagonist:  CGP 20712A)

Tissue Effects following β2-receptor activation Smooth muscle (including bronchial, vascular, GI and GU):  relaxation Skeletal muscle:  glycogenolysis and increased K+ uptake. Hepatic effects::  glycogenolysis and gluconeogenesis

Receptor type: β3

Agonist effectiveness:  Isoproterenol = Epinephrine > Norepinephrine (antagonist ICI 118551); BRL 37344 (antagonist:  CGP 20712A)

Tissue Effects following β3-receptor activation Adipose:  lipolysis

 

 

Dopamine Receptors^49,46

Receptor type: Dopamine (includes D1, D2,D3, D4,D5 )

example D1 agonist: fenoldopam; example D2 agonist:  bromocriptine

example D4: antagonist: clozapine

Signal transduction: D1:↑ cAMP; D2-D5: ↓cAMP

 

References

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242 Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260 Carotic Baroreceptors:  CRRx:  Mediine ReEnvisioned  http://www.cvrx.com/patients/index.php?id=41 Westfall, TC and Westfall DP Adrenergic Agonists and Antagonists in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 237-295, 2006. Catecholamine Biosynthesis:  The Interactive Library; Edinformatics.com:  http://www.edinformatics.com/interactive_molecules/info/adrenaline.htm . Standaert DG and Young AB Treatment of Central Nervous System Degenerative Disorders In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp536-537. Adrenergic Neuronal Diagram adapted from http://www.drugabuse.gov/pubs/teaching/Teaching4/Teaching.html Guanetidine (Ismelin™, brand name not available in the U.S.) pharmacology:  Clinical Pharmacology, RxList:  The Internet Drug Index, http://www.rxlist.com/ismelin-drug.htm . Williams FM and Turner TJ Adrenergic Pharmacology in Principles of Pharmacology:  The Pathophysiologic Basis of Drug Therapy, 2nd Edition (Golan DE, Tashijan Jr AH, Armstrong EJ and Armstrong AW, eds) Wolters Kluwer-Lippincott Williams & Wilkins, Philadelphia, 129-144, 2008. Moss J and Glick D Autonomic Function in Anesthetic Pharmacology:  Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 209-226, 2004. Presynaptic Proteins, Synaptic Vesicle Docking and Membrane Fusion, http://neuromuscular.wustl.edu/pathol/snare.htm#cachan, Neuromuscular Disease Center, Washington University, St. Louis, MO USA (http://neuromuscular.wustl.edu/index.html) Sudhof TC The Synaptic Vesicle Cycle, Annual Review of Neuroscience, July 200, Vol. 27, pp 509-547. Phenochomocytoma picture (http://health-pictures.com/pheochromocytoma.htm); Geneva Foundation of Medical Education and Research, Pheochromocytoma, http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=1&cat2=113&cat3=22&cat4=2&stype=n . Brown H, Goldberg PA, Selter JG, Cabin HS, Marieb NJ, Udelsman R and Setaro JF Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension. Clinical Case Seminar, J Clin Endocrinol Metab 2005 90: 563-569. (http://jcem.endojournals.org/cgi/content/full/90/1/563). "Clevidine (Cleviprex) for IV Treatment of Severe Hypertension", Table 1.  Some Parenteral Drugs for Hypertensive Emergencies.  The Medical Letter® on Drugs and Therapeutics, Volume 50 (Issue 1295) September 22, 2008. Katzung, BG Introduction to Autonomic Pharmacology (Section II: Autonomic Drugs) in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 75-92, 2007. Sympathetic Nerve Pathway:  Neuroeffector Junction ("Simplified diagram of a sympathetic neuroeffector junction displaying genes which may be involved"); PharmGKb modified slightly to highlight uptake1, uptake-2, uptake 1 block, and location of intravesicular norephinephrine synthesis. (Pharmacogenomics Knowledge Base). http://www.pharmgkb.org/search/pathway/neurotransmitter/neuroeffector.jsp . T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal (2001) 1, 167-170. Tellioglu T, Robertson D (November 2001). "Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications". Expert Rev Mol Med 2001: 1–10. Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, Ganapathy V (Aug 1998). "Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta". J Biol Chem 273 (26): 15971–9. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. (Jun 2006). "Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.". Neuropharmacology 50 (8): 941–952. Bourne HR and von Zastrow M "Drug Receptors and Pharmacodyamics" Chapter 2 in Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 17-27, 2007. Muller M Lecture Material Online:  Lecture 6: "Cellular Communication" http://www.uic.edu/classes/bios/bios100/summer2003/lect06.htm. Bowman T and Jove R STAT Proteins and Cancer:  From the Molecular Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida http://www.moffitt.org/moffittapps/ccj/v6n6/dept6h.htm . Tong L, Warren TC, King J, Betageri R, Rose J, Jakes S (March 1996). "Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution". J. Mol. Biol. 256 (3): 601–10. Sadowski I, Stone JC, Pawson T (December 1986). "A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps". Mol. Cell. Biol. 6 (12): 4396–4408. Russell RB, Breed J, Barton GJ (June 1992). "Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains". FEBS Lett. 304 (1): 15–20. von Zastrow M and  Bourne HR "Drug Receptors and Pharmacodynamics" Chapter 2 in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ,  eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Powledge TM (2004) Nicotine as Therapy. PLoS Biol 2(11): e404. doi:10.1371/journal.pbio.0020404 (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020404) Green T, Heinemann SF and Gusella JF Molecular Neurobiology and Genetics:  Investigation of Neuron Function and Dysfunction (Review) Neuron, Vol. 20, 427-444, March, 1998 (Cell Press (c), 1998). Unwin N Nicotinic acetylcholine receptor at 9 Å resolution. J. Mol. Biol. 229, 1101-1124. Eyford, T Adenylyl cyclase http://proteopedia.org/wiki/index.php/Adenylyl_cyclase . 31 a. Hurley JH. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem. 1999 Mar 19;274(12):7599-602. 31 b, Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997 Mar 20;386(6622):247-53. Goodsell DS illustrator, The Scrips Research Institute, public domain work, http://en.wikipedia.org/wiki/Adenylate_cyclase . Ranganathan R, Ross E (1997). "PDZ domain proteins: scaffolds for signaling complexes.". Curr Biol 7 (12): R770–3 PDZ domain  http://en.wikipedia.org/wiki/PDZ_domain Biaggioni I and Robertson D Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9) in  in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Korte E "PIP2 cleavage by PLC to release IP3 and DAG", public domain, http://en.wikipedia.org/wiki/File:PIP2_cleavage_to_IP3_and_DAG.jpg . McVary KT A review of combination therapy in patients with benign prostatic hyperplasia, Clinical Therapeutics 2007 29 (3):  387-398. Caine M The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol. 1986; 136:  1-4. Shapiro E Hartanto V and Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate. 1992; 21:  297-307. Brittsan AG and Kranias EG Review:  Phosphlakmban and Cardiac Contractile Function. J. Mol Cell Cardiol 32. 2131-2139. Lomize A Phospholamban Pentamer, protein image from OPM database, public domain media (http://en.wikipedia.org/wiki/File:1zll_opm.gif) Foex P and Highan H. Myocardial Performance:  Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 284-2285, 2004. 42(a)  Weiss HR Effect of coronary artery occlusion on regional arterial and venous O2 saturation, O2 extraction, blood flow and O2 consumption in the dog heart. Circulation Research 47(3) 400-407, September 1980. Khouri EM Gregg DE and Rayford CR Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circulation Research 17(5) 327-437, November 1965. Epicardial Vessels:  Gray's Anatomy, 20th U.S. edition of Gray's Anatomy of the Human Body, originally publishedin 1918, public domain. Beta-2 Adrenergic Receptor, figure public domain (http://en.wikipedia.org/wiki/File:2RH1.png); original crystallographic citations: 45 (a) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). "High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. 45 (b) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). "GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function". Science 318 (5854): 1266–73. Westfall, TC and Westfall DP Neurotransmission:  The Autonomic and Somatic Motor Nervous System in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 137-181, 2006. Emorine LJ Marullo S Briend-Sutren MM Patey G Tate K Delavier-Klutchko C Strosberg AD Molecular characterization of the human β3-adrenergic receptor. Science, Vol. 245, No. 4922, Sep. 8, 1989, pp. 1118-1121. Walston J Silver K Bogardus C Knowler W Celi FS Austin S Manning B Strosberg AD Stern MP Raben N Sorkin JD Roth J Shuldiner AR Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic receptor gene.  New England J. of Medicine, Vol. 333 No. 6, August 10, 1995, pp. 343-347. Hoffman BB Adrenoceptor-Activating & Other Sympathomimetic Drugs in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 121-140, 2007.

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.