Chemistry of Beta-Blocker

Question 1

What are the effects of alpha-1 and alpha-2 adrenoceptors?

Answer 1

Alpha-1

• vasoconstriction
• GI smooth muscle relaxation
• Salivery secretion
• Hepatic glycogenolysis

Alpha-2

• NT inhibition release
• Platelet aggregation

Question 2

The main classification of adrenergic receptors are into _____ subtypes

All _____ receptors

Answer 2

alpha + beta

a₁ + a₂

B₁ + B₂ + B₃

G-protein coupled

Question 3

What are the effects of Beta-1 + Beta-2?

Answer 3

Beta-1

• Increase cardiac rate + force
• GI smooth muscle relaxation
• Lipolysis

Beta-2

• Vasodilatation
• Visceral SM relaxation
• Hepatic glycogenolysis
• Muscle tremor

Question 4

Consists of _____ which contain the binding site for agonists and antagonists

Asp-113, Ser-204 + Ser-207 interact with the hydrophobic domain.

Which hydrophobic domain + functional group do they interact with?

Answer 4

7 transmembrane hydrophobic α-helices

Asp-113 in third hydrophobic domain interacts with amino group of catecholamine

Ser-204 and Ser-207 in fifth hydrophobic domain interact with catechol hydroxy groups.

Question 5

Beta-blockers bind to B-adrenoceptors located in cardiac _____ tissue, _____ system + _____.

The heart has both Beta1 + Beta2 adrenoceptors. The predominant receptor type in no. + function is _____.

Beta-blockers prevent the normal ligand (noradrenaline + adrenaline from binding to the beta-adrenoceptor.

Answer 5

Nodal

Conducting

Contracting Myocytes

Beta-1

Question 6

Give an example of a 1^st generation Beta-Blocker

Answer 6

Dichlorisoprenaline

Blocked relaxation of bronchial smooth muscle by isoprenaline

Was shown to be a partial agonists

• Isoprenaline*
• Agonist at beta not alpha-adrenoceptors*
• For the treatment of bradycardia/heart block or bronchoconstriction*

Question 7

What is a partial agonist?

Answer 7

Cannot elicit maximal tissue response

Full Agonist = can elicit maximal tissue response

Intrinsic activity = maximum response to test agonist / maximum response to full agonist acting through same receptor

Question 8

In all antagonist, the _____ pharmacophore was key

Analogues were produced to explore the chemical linkage of _____ side-chain to the aromatic ring.

_____ proved most effective

Answer 8

Arylethanolamine

Ethanolamine

Oxymethylene proved most effective

Question 9

Optimum Beta-antagonist activity resided with branched alkylamine substituents.

2 best were isopropyl + tert-butyl

Question 10

Discuss clinical use of beta-blockers

Answer 10

Cardiac Effects

Decrease contractility (negative inotropy)

Decrease relaxation rate (negative lusitropy)

Decrease heart rate (negative chronotropy)

Decrease conduction velocity (negative dromotropy)

Vascular Effects

Smooth muscle contraction (mild vasoconstriction)

Question 11

Describe Structure Activity Relationship (SAR) of Cardioselective β-blockers

Answer 11

Question 12

Whata are the side effects of the 1st generation Beta-Blocker side effects?

Answer 12

Question 13

Third-generation beta-blockers: discuss role of additional drug binding groups

Answer 13

Question 14

Describe the synthesis of beta-blockers

Answer 14

2-step process (nucleophilic substitutions)

Question 15

Name each part of the arene when substituting

Answer 15