chemistry of beta blockers

: What are β-blockers, and what do they do?

• β-blockers are β-adrenergic blocking agents

• Block the effects of the hormone epinephrine (adrenaline)

• They lower heart rate, reduce force of contraction, and lower blood pressure,

• they also widen veins and arteries to improve blood flow.

How do β-blockers work at the molecular level?

• Competitive inhibition of β-receptors

• Counters the effects of catecholamines (e.g., epinephrine)

What are the two types of nervous systems in the peripheral nervous system?

• Cholinergic system (using acetylcholine)

• Adrenergic system (using adrenaline and noradrenaline)

How do the cholinergic and adrenergic systems work together in the peripheral nervous system?

• The balance between these two systems allows for fine control of various bodily functions

• Cholinergic (acetylcholine) and adrenergic (adrenaline/noradrenaline) systems have opposing actions at various tissues

What is the difference between adrenaline, noradrenaline, and acetylcholine?

• Adrenaline is a hormone

• Noradrenaline and acetylcholine are neurotransmitters

• Their actions at tissues are opposite

What is the function of the α-1 receptor?

• Smooth muscle contraction

• Mydriasis (pupil dilation)

What is the function of the α-2 receptor?

Mixed smooth muscle effects (depends on tissue type)

What is the function of the β-1 receptor?

Increased cardiac chronotropic (heart rate) and inotropic (contractility) effects

What is the function of the β-2 receptor?

Bronchodilation (relaxation of bronchial smooth muscle)

What is the function of the β-3 receptor?

Increased lipolysis (fat breakdown)

How does the sympathetic nervous system help maintain the body’s environment in response to stress?

• Sympathetic nerve stimulation releases noradrenaline

• Noradrenaline stimulates the adrenal gland, increasing the release of adrenaline

• This response is part of the body’s stress adaptation, preparing the body for a “fight or flight” response

what are the 2 types of adrenoceptors?

• alpha: a1+a2

• beta: b1,b2,b3

• both are g protein coupled receptors

What happens when Phospholipase C is activated?

• Phospholipase C activation leads to the formation of:

  • Ip3

  • (DAG)

• These molecules cause an increase in intracellular calcium levels

How does adenylate cyclase affect cAMP levels?

• Adenylate cyclase activation leads to an increase in cAMP levels

• Adenylate cyclase inactivation leads to a decrease in cAMP levels

• Adrenaline and noradrenaline switch on adenylate cyclase

What are G-protein coupled receptors (GPCRs)?

• Cell surface receptors that are embedded in the plasma membrane

• Also called membrane or transmembrane receptors

• Bind to extracellular molecules (e.g., hormones, neurotransmitters)

• Activate intracellular signaling pathways via G-proteins

Where are β1 and β2 receptors typically found, and what is their function?

• β1 receptors are mainly found in the heart (cardiac muscle)

• β2 receptors are mainly found in bronchial smooth muscle and blood vessels.

• Both α, β, and α/β receptors can contribute to vasodilation depending on receptor type and potency

How does the β1 receptor work at the molecular level?

• 7-transmembrane receptor (7-TM receptor)

• G-protein linked to adenylate cyclase

• ATP is converted to cAMP

• cAMP activates PKA (Protein Kinase A)

• PKA phosphorylates proteins, driving the cellular response

What are the endogenous agonists for adrenergic receptors, and what is the catechol ring structure?

• Endogenous agonists: Adrenaline (epinephrine), Noradrenaline (norepinephrine)

• Catechol ring structure:

  • Both adrenaline and noradrenaline have a catechol ring structure

  • Catechol ring consists of a benzene ring with two hydroxyl groups (-OH) at positions 3 and 4

What structural features are important for target binding in this SAR?

How do stereochemistry and substituents affect receptor selectivity and activity?

• R-enantiomer is more active than S

• Substitution at R increases α-receptor binding

• Larger R₂ substituents increase β-selectivity

Which molecules do not bind effectively to the receptor, and why?

• Tyramine ❌

  • Lacks key hydroxyl (OH) groups needed for hydrogen bonding

  • Weaker receptor interactions

• Amphetamine ❌

  • Missing aromatic ring OH groups

  • Reduced ability to bind to the receptor binding site

What was Dichloroisoprenaline (DCI) and why was it important?

• Prepared by Eli Lilly (1958)

• Catechol modified (3,4-dichloro) → agonist → antagonist

• Became the first β-blocker

• Acted as a partial agonist

• No clinical use, but an important lead compound

How did DCI lead to clinically useful β-blockers?

• Sir James Black used sympathetic nerve stimulation assays

• Replaced dichloro groups with a carbon bridge

• Formed a naphthylethanolamine derivative

• Led to pronethalol (1962)

• Pronethalol: β-blocker, only weak partial agonist

What was pronethalol used for clinically?

• First clinically available β-blocker

• Used to treat:

  • Hypertension

  • Angina

  • Certain cardiac arrhythmias

• Only marketed for life-threatening conditions

Explain why pronethalol was eventually withdrawn from the market, and what impact did this withdrawal have on beta-blocker development?

• Pronethalol was withdrawn due to toxicology concerns, specifically the observation of thymic tumors in rats.

• This spurred further research into the structural features of beta-blockers to find safer alternatives.

How did the chemists at ICI initially stumble upon the increased potency of propranolol during their research of pronethalol?

1. While originally aiming to create a compound better than pronethalol, the chemists used an α-naphthol rather than the intended β-naphthol during the synthesis process, unexpectedly leading to the creation of a compound 20x more potent.

What are epoxides and why are they reactive?

• 3-membered ring containing an oxygen atom

• Highly strained structure

• Carbon atoms are electrophilic

• React readily with nucleophiles

Why does ring opening of epoxides occur easily?

• Ring strain (internal angle ≈ 60°)

• Ring opening relieves strain

• Provides strong thermodynamic driving force

• Reaction may be acid-catalysed

How do reaction conditions affect epoxide ring opening?

• Basic conditions / strong nucleophile → attack at less substituted carbon

• Acid-catalysed conditions → attack at more substituted carbon

• Regioselectivity depends on reaction conditions

What side effects were associated with 1st-generation β-blockers?

• Crossed the BBB → dizziness, sedation

• Caused bronchoconstriction (problematic in asthmatics)

• Lowered cardiac output

• Resulted in poor tolerability

Why and how was propranolol modified in later β-blocker development?

• Use of “back-up” compounds to improve safety

• Issue with propranolol: high lipophilicity (logP = 3.66)

• Leads to BBB penetration → CNS side effects

• Strategy to reduce logP:

  • Remove one aromatic ring

  • Add logP-lowering groups (e.g. acetamide, sulphonamide)

What were the advantages of practolol compared with propranolol?

• Contains an amide group → potential H-bonding

• More polar (logP ≈ 0.79)

• Reduced BBB penetration

• Fewer CNS side effects

• β₁-selective over β₂ (cardioselective)

• Less potent than propranolol but more selective

What were the clinical uses and limitations of practolol?

• Launched in 1970

• Used for:

  • Angina

  • Hypertension

  • Immediate post-myocardial infarction

• Withdrawn due to adverse effects:

  • Skin rashes

  • Eye problems

  • Peritonitis(swelling of the belly)

What are the key structural and pharmacological features of 2nd-generation β-blockers?

• Contain an extended para substituent

• Capable of hydrogen bonding

• β₁-selective (cardioselective)

• Fewer side effects than 1st-generation agents

• Reduced CNS effects due to increased polarity

What are the clinical considerations for 2nd-generation β-blockers?

• Some activity on smooth muscle (β₂)

• Use with caution in asthmatics

• Acebutolol is a partial agonist

• Partial agonism →

  • Less bradycardia

  • Reduced cold extremities

How do 1st-generation β-blockers contrast with later generations in terms of safety?

• Cause bronchoconstriction → dangerous in asthmatics

• Reduced cardiac output → fatigue, limb tiredness

• CNS effects due to BBB penetration:

  • Dizziness

  • Nightmares

  • Sedation

• Cold extremities (poor peripheral circulation)

• Can precipitate heart failure

• Excessive reduction in resting heart rate → risk in patients near myocardial infarction

How were short-acting β-blockers developed?

• Introduction of labile ester functionality

• Aim: rapid hydrolysis → short duration of action

• Aryl esters hydrolysed too slowly

• Aromatic ring acts as steric shield

• Led to identification of esmolol

How do esmolol and landiolol compare?

• Landiolol has ~7-fold higher β₁-selectivity than esmolol

• 8–12× more potent than esmolol

• Greater cardioselectivity

• Improved control and safety in acute settings

What characterises 3rd-generation β-blockers?

• Example: carvedilol

• Used in congestive heart failure

• Contain an extended amine substituent

• Interact with additional regions of the β₁-receptor

• Improved selectivity

• logP carefully balanced to reduce side effects

1. What is the significance of LogP in drug design, and how was it utilized to modify propranolol to reduce side effects?

1. LogP is the logarithm of a compound's partition coefficient and indicates its lipophilicity.

2. By reducing the LogP value through structural modifications like the addition of polar acetamide and sulfonamide groups, researchers could improve the drug's selectivity and reduce CNS-related side effects.

1. What is the key difference in the structural design of the 2nd and 3rd generation beta blockers, and how do these changes affect selectivity and potency?

1. 2nd generation beta-blockers contain an extended para-substituent capable of H-bonding, enhancing β1 selectivity

2. while the 3rd generation beta blockers incorporate an extended amine substituent designed to interact with another part of the β1 receptor and further improving selectivity.use extension strategy to gain extra H-bonding with β1