A Study on Beta Blockers - a Brief Review Tv

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IJRPC 2018, 8(4), 508-529 Namratha et al. ISSN: 22312781

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Available online at www.ijrpc.com Review Article

A STUDY ON BETA BLOCKERS - A BRIEF REVIEW TV. Namratha*, KC. Chaluvaraju and AM. Anushree Department of Pharmaceutical Chemistry, Government College of Pharmacy, Bengaluru-560 027, Karnataka, India.

ABSTRACT Beta blockers are agents or drugs which competitively inhibit the action of catecholamines at the beta adrenergic receptors, which are mainly used to treat variety of clinical conditions like angina, hypertension, asthma, COPD and arrhythmias. These drugs are also useful in several other therapeutic situations including shock, premature labor and opioid withdrawal, and as adjuncts to general anesthetics. These drugs produce their effect by interacting with the beta adrenergic receptors. In the present communication, an effort has been made to compile beta adrenergic receptors and the chemistry, discovery and development, classification and therapeutic applications of beta blockers.

Keywords: Beta blockers, adrenergic receptors, catecholamines and aryloxypropanolamines.

1. INTRODUCTION Beta blockers were first developed by Sir 1.1 Adrenergic receptors James Black in 1962. The structures of The ability of a molecule to selectively these receptors have been studied by x- agonize or antagonize adrenergic ray crystallography.5 In the current article receptor made great advances in beta blockers are majorly focused with pharmacotherapeutics. The discovery of respect to their location, functions adrenergic receptors lead to major mediated, discovery and development, development of newer adrenergic SAR, classification, structures and agonists as well as antagonist.1 therapeutic applications. Adrenergic receptors are 7- transmembrane spanning receptors 1.2 Locations and agonistic action of beta which mediate both central and adrenergic receptors6 peripheral actions of the adrenergic The following are the various beta neurotransmitters. Adrenergic receptors adrenergic receptors found in different are found in nearly all peripheral tissues physiological locations and their actions and on many neurons within the central mediated by their stimulation with beta nervous system.2 They play an important adrenergic agonists. (Table 1) role in the control of blood pressure, myocardial contractile rate and force, 2. DISCOVERY AND DEVELOPMENT OF airway reactivity, and a variety of BETA ADRENERGIC ANTAGONISTS metabolic and central nervous system One of the beta adrenergic agonist functions.3 drugs, Isoprenaline (Fig. 1), was In 1948, Raymond P. Ahlquist classified considered as a lead molecule. It is a the adrenergic receptors into two major beta receptor agonist but has no action types i.e. α and β, based on their on alpha receptors. This lead molecule pharmacological characteristics such as was studied in depth and suitable rank order of potency of agonists.4 structural modifications required for beta Subsequently, both α and β types were adrenergic antagonistic activity were 3 subdivided into α1, α2, β1, β2 and implemented. β3subtypes respectively. Further, based The first such modifications carried out on pharmacological and molecular included was the replacement of the evidences alpha receptor subtypes were phenolic hydroxyl groups in isoprenaline classified into α1A, α1B, α1D. with chloro substituents gave

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dichloroisoprenaline (Fig. 2), which is a 3.2 Based on their chemical nucleus partial agonist. Beta blockers can be classified This promising molecule into: dichloroisoprenaline gave an insight in 1. Arylethanolamines next stage of development to convert the Ex: pronetalol, sotalol, labetalol, beta adrenergic agonistic activity into brefonalol, Bufuralol antagonistic activity. The general 2. Aryloxypropanolamines methodology to do so was to introduce Ex: Propranolol, esmolol, metoprolol, another aromatic ring into the existing acebutalol, atenolol molecule. This resulted in a drastic change in hydrophobic interaction of the molecule with the receptor and also 3.3 FDA classes of beta blockers for changed the induced fit between the use in pregnant women 7,8 ligand and the binding site. This new fit A. Category A resulted in binding of ligand to the Adequate and well-controlled studies receptor’s binding site but without the have failed to demonstrate a risk to activation of the same. the fetus in the first trimester of Considering the above fact, the chloro pregnancy (and there is no evidence groups were replaced with a benzene of risk in later trimesters). ring, to form a rigid naphthalene ring No β-blockers is completely safe for system. This gave pronethalol (Fig. 3), using during pregnancy. the first beta blocker to be used clinically to treat angina, arrhythmia and B. Category B hypertension.5 Though, it exhibited great Animal reproduction studies have therapeutic activity, it was soon failed to demonstrate a risk to the withdrawn due to its carcinogenic effects. fetus and there are no adequate and 6 well-controlled studies in pregnant The further development was a result of women. the introduction of side chains between Eg. Pindalol, acebutalol, sotalol the naphthalene ring and the ethanolamine. The discovery of C. Category C propranolol (Fig. 4) was in fact a result of Animal reproduction studies have an accident during the synthesis for shown an adverse effect on the fetus which α-naphthol was used in the and there are no adequate and well reaction mixture instead of the β- controlled studies in humans, but naphthol and a drug having structure potential benefits may warrant use of with side chain at C1 of the naphthalene the drug in pregnant women despite ring rather than the C2 was obtained. potential risks. Propranolol is a pure antagonist and this Eg. Labetalol, Bisoprolol, Timolol, molecule is considered to be a bench Metoprolol mark in evaluation of all other beta blockers. D. Category D There is positive evidence of human 3. CLASSIFICATION OF BETA fetal risk based on adverse reaction BLOCKERS data from investigational or marketing 3.1 Beta blocking agents are classified experience or studies in humans, but into 3 classes based on selectivity and potential benefits may warrant use of action: the drug in pregnant women despite 1 First generation-Non selective in potential risks. nature and cause no vasodilation Eg. Atenolol Ex: Propranolol, Nadolol, Pindolol 2 Second generation - cardioselective 4. STRUCTURE ACTIVITY in nature RELATIONSHIP OF Ex: Acebutolol, atenolol ARYLOXYPROPANOLAMINES 3 Third generation–Non selective Presently, aryloxypropanolamines are agents which cause vasodilation the most commonly used beta Ex: Primidolol, Epanolol adrenergic blockers. Though the beta blockers are marketed in the racemic form, typically the activity lies only in one of its isomeric form. In arylethanolamines, the activity was

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found to reside in the (R) form, while receptors by the neurotransmitters, in case of aryloxypropanolamines, it results in the production of cAMP by resides in the (S) form.9 adenyl cyclase. cAMP is a secondary Following are the necessary structural messenger molecule which activates requirements for their optimum activity: 4 the Protein Kinase A (PKA). The  Presence of branched N-alkyl action of PKA is to increase the functional moieties. This fits into the calcium release which is responsible hydrophobic pockets, both branching for the physiological action. Beta and extension of this alkyl side chain blockers act by binding to the beta is essential. adrenergic receptors and blocking the  Presence of hydroxyl group on the action of neurotransmitters. (Fig. 5) side chain is essential for the hydrogen bonding with receptors. 6. BETA ADRENERGIC  Presence of amino group is essential BLOCKERS10-25 and it should be secondary in nature, Various beta adrenergic blockers, and it is required for the ionic bonding their structures, molecular formula, interaction. molar mass and therapeutic uses are  Presence of oxymethylene bridge is discussed here. also essential for the drug to bind to The following are the most widely the receptor. used beta adrenergic blockers: (Table 2). However, the following changes are feasible:  The aromatic ring system can be 7. CONCLUSION heterocyclic in nature. Beta blockers constitute an important  Aryloxy substitution can be at C2 class of drugs in the clinical treatment which gives more potent compounds of various disorders like hypertension, than those substituted at C1 angina pectoris, asthma, glaucoma  Variation in lipophilicity can be and arrhythmias. Various physical achieved by introducing suitable and chemical parameters of beta substituents. adrenergic antagonists such as the specificity, solubility, permeability and The following modifications were found to be distribution of the molecule can be detrimental and lead to loss of activity: modified in order to obtain a drug with  Introduction of substituent on the preferred characteristics. Study of the propyl side chain. nature and type of receptor at the  Replacement of the ethereal oxygen target tissue, and also by analyzing with S, CH2 or N-CH3. the structure activity relationship helps in obtaining molecules with 5. MECHANISM OF ACTION OF BETA optimum biological and BLOCKERS 6 physiochemical properties. Beta receptors are G protein coupled receptors. Activation of these

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TABLES

Table 1: locations of beta adrenergic receptors and actions of beta adrenergic agonists TYPE OF RECEPTOR LOCATION PHYSIOLOGICAL EFFECT

β1 Myocardium Increase in contractility and heart rate Blood vessel Coronary vasodilation Kidney Increase in renin release Fat tissue Stimulation of lipolysis β2 Myocardium Increase in contractility and heart rate Smooth muscles in bronchi Bronchodilation Smooth muscles in blood vessels Vasodilation Smooth muscles in genitourinary tract Relaxation Smooth muscles in large intestine Relaxation Fat tissue Stimulation of lipolysis Liver Glycogenolysis and glyconeogenesis Pancreas Stimulation of insulin release Sympathetic nerve terminals Stimulation of noradrenaline release Skeletal muscles Less fatigue( due to aerobic respiration) Tremors Blood lipids Low triglycerides and high HDL Eye Increase in intraocular pressure

β3 Fat tissue Stimulation of lipolysis and thermogenesis Myocardium Cardiodepression Blood vessels Vasodilation Genitourinary smooth muscles Muscle relaxation

Table 2: List of beta blockers and their properties and uses Sl. Compound Molecular Molecular Therapeutic Structure No. Name Formula Mass uses O O NH CH CH 3 3 336.426 Hypertension 1 Acebutalol C H N O 18 28 2 4 g/mol and arrhythmia

O NH CH3

CH3 OH OH

O NH CH3 O 429.59 2 Adaprolol C H NO Glaucoma 26 39 4 g/mol CH3 O

CH3 O HO NH NH N CH3 O 419.52 3 Adimolol C H N O Antihypertensive 25 29 3 3 g/mol

O O OH CH 3 279.33 4 Alfurolol O NH C H NO - 15 21 4 g/mol

CH3 H3C

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OH Antihypertensive O NH CH , in edema, 3 249.34 5 Alprenolol C H NO ventricular 15 23 2 g/mol tachycardia and atrial fibrillation CH3 CH 2 CH2

It is a prodrug to alprenolol.Antihy O CH pertensive, in 3 262.35 6 Alprenoxime C H N O edema, 15 22 2 2 g/mol ventricular tachycardia and NH CH3 atrial fibrillation N OH CH3 O O OH NH Antihypertensive 380.45 prior to C H N O g/mol operations in 7 Amosulalol 18 24 2 5 S patients with O pheochromocyto ma S NH O 2 CH3

H3C CH3 HN CH3 HO

C H N O 332.39 8 Ancarolol 18 24 2 4 Antihypertensive g/mol O NH O

OH CH O 3 253.34 9 Arnolol C H NO - NH 14 23 3 g/mol H C 2 H3C 3 O

HO CH3 NH S N 371.54 CH3 Treatment of g/mol H3C C H N O high blood 10 Arotinolol 15 21 3 2 S S pressure and es H N 3 2 S sential tremor.

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H3C

HN CH Used primarily 3 in cardiovascular 266.336 11 Atenolol C H N O diseases. HO 14 22 2 3 g/mol O Treatment for hypertension

H2N O CH3

CH 3 O NH CH3 Management C H NO 291.342 12 Befunolol O OH 16 21 4 of open-angle g/mol O glaucoma.

O NH CH3 Treatment 307.428 13 Betaxolol C H NO of hypertension 18 29 3 g/mol CH3 and glaucoma O

CH3 OH

O NH O CH3 Treatment of 345.43 14 Bevantolol C H NO angina and 20 27 4 g/mol O hypertension

CH3

OH High blood O NH CH3 pressure, chest CH 325.443 pain from not 15 Bisoprolol 3 C H NO 18 31 4 g/mol enough blood O CH3 H C O flow to the heart, 3 and heart failure

CH3 H3C O NH H3C O C H N O 380.48 Angina pectoris, 16 Bopindolol 23 28 2 3 O g/mol Hypertension

CH3 N H

OH 303.45 g/mo 17 Bornaprolol C H NO Antihypertensive 19 29 2 L O NH CH3

CH3

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H C 3 352.48 g/mo 18 Brefonalol CH C22H28N2O2 l - HN 3

H N O OH

H N 363.45 19 Bucindolol C H N O - O 22N 25 3 2 g/mol H3C NH

OH CH3

O OH 305.37 g/mo CH3 20 Bucumolol O NH C17H23NO4 l Antihypertensive

CH3 H3C H3C

OH O

CH HN 3 323.43 g/mo 21 Bufetolol O C18H29NO4 l Antiarrhythmic

CH3 H3C

H C Peripheral 3 261.37 g/mo vasodilating, 22 Bufuralol CH3 C H NO 16 23 2 l antianginal and O antihypertensive H3C NH CH3 OH N OH CH 248.33 g/mo Antianginal and 23 Bunitrolol 3 C H N O O NH 14 20 2 2 l antiarrhythmic

CH3 H3C

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N 178.24 g/mo 24 Bupicomide NH2 C10H14N2O l Antihypertensive

H3C

Cl OH CH O NH 3 Treat hypertensi C H ClNO 271.78298 25 Bupranolol CH 14 22 on and tachycar 3 g/mol H3C 2 dia

CH 3 H3C O

CH H3C 3 CH3 267.364 26 Butaxamine C H NO - 15 25 3 g/mol

NH CH3 O OH H C 3 OH

NH 247.38 g/mo 27 Butidrine C H NO Local anesthetic CH3 16 25 l

CH3

F CH 3 Treatment 311.392 28 Butofilolol H3C C H FNO of essential 17 26 3 g/mol hypertension CH3 O NH CH3 OH

H3C

CH3 HN CH3 HO 408.58 O g/mol 29 Capsinolol NH C23H40N2O4 In tachycardia

O H3C

CH3 O O NH 348.44 C H N O g/mol 30 Carpindolol H3C C19H3 28 2 4 - H3C O N H H3C

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Glaucoma (open HN O -angle type) or other eye diseases (such C H N O 292.373 31 Carteolol 16 24 2 3 as ocular g/mol hypertension), HO antihypertensive, CH HN 3 antiarrhythmic, antianginal. CH H C 3 3 Used for treating mild to severe congestiv CH3 e heart failure (CHF), lef OH 406.474 t ventricular 32 Carvedilol HN O C24H26N2O4 O g/mol dysfunction (LV NH D) O following heart attack and for treating high blood pressure. OH CH O NH 3 Treatment O of high blood CH pressure and 3 379.49 33 Celiprolol O H3C C H N O treatment of 20 33 3 4 g/mol H3C N NH vascular Ehlers– Danlos CH3 syndrome. H3C

CH3 HN O

310.39 g/mo 34 Cetamolol C H N O - O OH 16 26 2 4 l CH O NH 3

CH3 H3C

O NH CH3 323.43 g/mo 35 Cicloprolol C H NO In tachycardia 18 29 4 l O CH3 O

O O H3C

OH 293.36 36 Cinamolol C H NO - 16 23 4 g/mol O NH CH3

CH3

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OH CH Cl O NH 3 C H Cl N 292.20 g/mo 37 Cloranolol 13 19 2 Antiarrhythmic O2 l CH3 H3C Cl N

HO CH3 287.36 38 Cyanopindolol NH C16H21N3O2 - HN O g/mol

CH3 H3C

CH3 H3C OH N 318.41 N g/mol 39 Dalbraminol O NH C H N O - NH 17 26 4 2

CH3

CH3 HO CH 3 Active Desacetylmetipr C15H25NO3 267.37 g·mo 40 −1 metabolite of anolol l metipronolol H3C O NH CH3

CH3 OH

Cl NH CH C H Cl N Dichloroisopren 3 11 15 2 248.15 41 O - aline g/mol

CH3 Cl OH

O NH CH3

Dihydroalprenol C H NO 251.37 g/mo Alprenolol 42 15 25 2 ol CH3 l derivative

CH 3

O OH 369.51 g/mo New class I C C H NO 43 Diprafenone CH323 31 3 l antiarrhythmic O NH agent

H3C CH3

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OH CH O NH 3 CH3 CH3 O N H3C 410.51 C H N O g/mol 44 Draquinolol 24 30 2 4 -

CH3

O H3C O 483.56 N HN g/mol 45 Ecastolol O C26H33N3O6 -

CH3 O NH O OH

N OH 369.41432 g/mol 46 Epanolol NH C20H23N3O4 New antianginal O NH OH O

OH C H ClNO Antihypertensive 18 24 337.84 47 Ericolol CH3 , antianginal and O NH 3 g/mol antiarrhythmic

CH3 H3C

O N N

NH C21H26N4O5 446.52 g/mo 48 Ersentilide S l Antifibrillatory

NH O OH O S CH O 3

H3C O

295.374 O CH3 C H NO g/mol Class II 49 Esmolol 16 25 4 antiarrhythmic

O NH CH3 OH

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H2C CH3

O H3C O 387.47 C H NO g/mol 50 Eugenodilol 22 29 5 - O O NH OH

CH3

O NH CH3 291.44 g/mo 51 Exaprolol C H NO - HO 18 29 2 l

CH3

O NH H3C CH3 228.34 g/mo Treatment of 52 Falintolol C H N O 12 24 2 2 l glaucoma N CH3

H C 3 NH O HO NH CH 3 NH2

O C H FN O 327.36 g/mo In angina and 53 Flestolol 15 22 3 4 l atrial fibrillation O

O Antihypertensive O CHC3 H FNO 391.48 g/mo 54 Flusoxolol 22 30 4 , antianginal and l antiarrhythmic O NH CH3 OH

OH CH O NH 3 308.37 Active Hydroxycarteolo C H N O g/mol 55 CH163 24 2 4 metabolite of l H C 3 carteolol O N H OH

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H3C CH3 O NH CH3 Hydroxytertatolo 311.44 56 S OH C H NO S - l 16 25 3 g/mol

277.402 CH3 CH3 g/mol 57 ICI-118,551 C17H27NO2 -

H3C O NH CH3 OH

O NH CH3 261.36 58 Idropranolol C H NO - 16 23 2 g/mol CH3

O NH CH3 247.34 g/mo 59 Indenolol C H NO Antiarrhythmic 15 21 2 l CH3

O 374.86 Cl O NH C H ClN g/mol 60 Indopanolol 20 23 2 - O3 NH OH

H3C

I Used in mapping OH the distribution Iodocyanopindol 413.25 61 C H IN O of beta ol CH3 16 20 3 2 g/mol HN O NH adrenoreceptors in the body CH3 H3C

I HO Used in mapping the distribution NH CH 374.22 g/mo 62 Iodopindolol HN O 3 C H IN O of beta 14 19 2 2 l adrenoreceptors in the body CH3

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O HO H3C

O CH 349.38 63 Iprocrolol O NH 3 C H NO Antiarrhythmic 18 23 6 g/mol O OH

CH3

Used in scientific research. It acts N OH as an antagonist 274.357 64 Isamoltane C H N O at the β- O 16 22 2 2 g/mol NH CH3 adrenergic, 5- HT1A, and 5- HT1B receptors. H3C

H3C N O 330.42 g/mol Antiarrhythmic 65 Isoxaprolol C19H26N2O3 and OH antihypertensive CH O NH 3

CH3 H3C

OH CH3 328.406 C OH N O g/mol 66 Labetalol 19 24 2 3 Antihypertensive NH

CH3 NH2

H C O 3 O O Landiolol H C 509.59 Antiarrhythmic 67 3 O NH N C25H39N3O8 O NH g/mol agent

OH O

H3C CH3 O NH CH3 Topically to OH 291.385 68 C H NO manage glauco 17 25 3 g/mol Levobunolol ma

O O OH O

NH 372.415 69 Medroxalol O C20H24N2O5 Vasodilator NH2 g/mol

CH3 OH

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H3C HO

NH CH3 HN O 262.35 g·mo To 70 Mepindolol C H N O −1 15 22 2 2 l treat glaucoma

CH3

O CH3 H3C O H3C 309.401 To 71 Metipranolol C H NO 17 27 4 g/mol treat glaucoma NH CH H3C O 3

CH3 OH

To treat high blood pressure, chest O H3C pain due to poor H3C blood flow to the 267.37 g·mo heart, and 72 Metoprolol CCH15H25NO3 −1 O NH 3 l arrhythmia. Trea tment of post OH myocardial infarction patients and also in migraine.

CH3 To 239.32 g·mo treat hypertensio 73 Moprolol C13H21NO3 −1 O NH CH l n, anxiety, 3 and glaucoma O HO H C 3 OH Treatment of high blood HO pressure and ch OH est pain. Additionally, in

CH 309.401 the treatment 74 Nadolol 3 C H NO O NH 17 27 4 g/mol of atrial fibrillation, migrai CH3 ne headaches, H3C and complications of cirrhosis. F

Treatment F 75 O of hypertension C H F NO 405.435 Nebivolol 22 25 2 and left g/mol 4 ventricular O NH failure. OH OH

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NH CH3 224.26 g·mo Treatment of 76 Nifenalol C H N O 11 16 2 3 l−1 angina O + CH3 N - O OH

O O NH CH3 O 326.35 g·mo In treatment of 77 Nipradilol C15H22N2O6 −1 + l glaucoma - N CH3 O O

OH Treatment O NH CH of angina 3 pectoris, 78 Oxprenolol C H NO 265.348 15 23 3 abnormal heart r hythms and high CH2 CH3 blood pressure. O OH O NH O CH3 396.49 g·mo Long acting 79 Pacrinolol CC23HH328N2O4 −1 O l antihypertensive. N CH3

O NH CH3 CH3 O 337.46 g·mo 80 Pafenolol C H N O −1 Antihypertensive 18 31 3 3 l CH3 H3C NH NH

O NH CH3 O 310.39 g·mo Antihypertensive 81 Pamatolol C H N O 16 26 2 4 l−1 drug H3C CH3 O NH

O OH 277.36 g·mo 82 Pargolol C H NO −1 - CH 16 23 3 l O NH 3

CH3 H3C

OH Treatment 291.428 83 Penbutolol CH3 C H NO of high blood O NH 18 29 2 g/mol pressure

CH3 H3C

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OH CH HN O NH 3 O Br

C23H34BrN3 480.45 g·mo CNS depressant 84 Pindobind H C −1 3 O3 l drug in animals NH

CH3

HO Treatment HN O NH CH3 248.321 of hypertension 85 Pindolol C H N O 14 20 2 2 g/mol and angina pectoris CH3

OH Emergency O NH CH treatment 3 of cardiac O 266.336 86 Practolol C H N O arrhythmias. 14 22 2 3 g/mol Practolol is no CH3 longer used as it H3C NH is highly toxic

CH3 OH

O NH CH3 N 333.39 g·mo 87 Primidolol C H N O −1 Antihypertensive 17 23 3 4 l O N O H

OH 249.35 g·mo 88 Procinolol C H NO −1 Antiarrhythmic O NH CH3 15 23 2 l

CH3

OH NH CH Never used 3 229.32 clinically due 89 Pronethalol C H NO 15 19 g/mol to carcinogenicit y CH3

To treat hypertensio n, arrhythmia, thyro toxicosis, capillar y HO hemangiomas, p erformance

anxiety, O NH CH 259.34 90 Propranolol 3 C H NO essential 16 21 2 g/mol tremors, to prevent migraine CH3 headaches, further heart problems in those with angina or previous heart attacks

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N Cl OH NH O NH C15H18Cl2N4 373.23 g·mo 91 Ridazolol NH O −1 - O3 l Cl

H3C

CH3 NH

358.44 g·mo 92 Ronactolol C H N O −1 - 20 26 2 4 l NH O OH O

H3C O

N OH

CH3 306.41 g·mo 93 C H N O −1 - Soquinolol O NH 17 26 2 3 l

CH3 H3C

NH CH3 C H N O 272.3624 Class III Sotalol O 12 20 2 3 94 S g/mol antiarrhythmic H3C drug S CH3 NH O

345.48 g·mo In control of C H NO −1 95 Spirendolol 21 31 3 l essential H3C tremors CH3 O NH CH3 HO H3C OH

325.45 g·mo SR 59230A O NH C H NO 96 21 27 2 l−1 -

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CH3 O O OH Sulfinalol 377.50 g·mo −1 97 S NH C20H27NO4S l Antihypertensive H3C

CH3 HO

OH H3C CH3 NH

CH3 363.50 g·mo Talinolol −1 98 O C20H33N3O3 l - O

NH NH

S CH3 216.30 g·mo Tazolol C H N O S −1 Treatment 99 9 16 2 2 l N of heart disease. NH CH3

H C 3 295.44 Tertatolol CH3 C H NO S 100 16 25 2 g/mol Antihypertensive O NH CH3 S HO

OH CH NH 3

CH3 S O H3C 420.52 g·mo Tienoxolol [ C H N O −1 101 21 28 2 5 l Diuretic S

O CH3 O NH O

OH CH3 H3C O NH N CH Tilisolol 3 C17H24N2O3 304.38 102 H C Vasodilator 3 g/mol O

O Antihypertensive ,treatment of chest pain due to insufficient blood flow to the C H N O 316.421 Timolol N 13 24 4 3 heart, also used 103 OH S g/mol to prevent

O further NH CH3 complications N after a heart attack, and S N H C CH3 migraines 3 prevention.

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CH3 S OH 255.38 g·mo Tiprenolol C13H21NO2S −1 104 O NH CH3 l -

CH3

OH NH2 344.41 g·mo Tolamolol C H N O −1 19 24 2 4 l 105 H3C O NH - O

H3C O NH CH3 223.32 g·mo Toliprolol C13H21NO2 −1 106 l -

CH3

CH3 OH CH3 H3C O NH 251.36 Xibenolol C15H25NO2 107 g/mol - CH3

H3C

CH3 OH

O NH CH3 Xipranolol C23H33NO2 355.51 108 Antiarrythmic H3C g/mol CH3 CH3 H3C

FIGURES OH

HO NH CH3

CH3 HO Fig. 1: Chemical structure of isoprenaline

Cl NH CH3

CH3 Cl Fig. 2: Chemical structure of dichloroisoprenaline

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NH CH3

CH3

Fig. 3: Chemical structure of pronethalol

O NH CH3

CH3

Fig. 4: Chemical structure of propranolol

Fig. 5: Mechanism of action of nor adrenaline on beta adrenergic receptors.11

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