1. Adrenergic Acting Drugs Pharmaceutical Medicinal Chemistry-I
Dr. Bilal Al-Jaidi
Assistant Professor in Medicinal Chemistry and Drug Design
Faculty of Pharmacy, Philadelphia University-Jordan

2. Learning Outcomes At the end of this lesson, students will be able to:
Define the biochemistry and Physiology of Sympathetic system.
Classify the difference between agonist and antagonist agents of Adrenergic receptors
Outline the SAR of Catecholamines.
Demonstrate the history of bronchodilators
Explain the use of adrenergic agonists and antagonists in disease management.
Demonstrate the structural differences between agonists and antagonist at the molecular level.

3. Drugs acting on adrenergic NS
Adrenaline and noradrenaline are the N.T.

4. Physiological Actions
Adrenaline:
Stimulates the heart.
Dilate blood vessels going to muscles.
Smooth muscle relaxation of GIT and bronchi.
Noradrenaline:
Same as adrenaline but it constrict blood vessels going to skeletal muscles

5. Adrenergic Receptors  receptors. β receptors.
1 : in bronchial smooth muscles, GIT, liver and veins.
2 : in GIT
β receptors.
β1: in heart muscles.
β2: in bronchial muscles, veins, kidney, liver and blood vessels to skeletal muscles.
β3: in fat cells.

6. Activation of Adrenergic Receptors
Activation of  receptors contracts smooth muscles except in GIT.
Activation of β receptors relaxes smooth muscles (for β2), whereas activation of β1 contracts the heart.
The overall effect of adrenaline is to increase blood pressure (at the same time increase blood flow to skeletal muscles (which have β2 receptors).

8. belong to catecholamines group.
Synthesized from L-tyrosine through dopamine.

9. L-Tyrosine Hyroxylaze is the rate limiting
enzyme in this pathway

10. They are catecholamines compounds

11. Noradrenaline and adrenaline
At physiological pH, more than 95% ionized.
Chemically unstable

12. Mechanisms of termination:
Reuptake mechanism: by energy-requiring pump present in presynaptic membrane. This pump is the site of action of cocaine and tricyclic antidepressents.
Metabolized by MAO and COMT in liver.

13. NE Reuptake

14. MAO and COMT
MAO (Monoamine oxidase):

15. MAO and COMT
COMT (Catecholamine O-methyl transferase):

16. Chemical stability inside body
Catecholamines are chemically stable inside different body compartments.
In blood they will be protonated

17. Drugs affecting adrenergic system
Affecting Noradrenaline storage
Affecting Noradrenaline interaction with receptors
Affecting Noradrenaline reuptake
Affecting MAO or COMT
Affecting Noradrenaline synthesis
Affecting Noradrenaline release

18. Drugs affecting adrenergic system
Drugs inhibiting catecholamine biosynthesis:
Inhibits L-tyrosine hydroxylase (rate limiting step).
Used in pheochromocytoma (tumor causing excessive production of adrenaline and noradrenaline.

19. Drugs affecting adrenergic system
Drugs affecting catecholamine storage:
Inhibits transporter protein of noradrenaline to be stored in the storage vesicles.
Used in hypertension.

20. Drugs affecting adrenergic system
Drugs preventing noradrenaline release from neuronal storage vesicles:
Very basic (pka = 12)….. Completely protonated at physiological pH.
Few CNS side effects (why?).
Used in hypertension.
Guanadril is 85% orally bioavailable while guanethidine is 3-50% (why?).

21. Drugs affecting adrenergic system
Sympathomimetic agents: directly bind to the adrenergic receptors in the postsynaptic membrane.
SAR of catecholamines:
Catechol ring is important.
β-hydroxyl group is important.
Stereochemistry at β position should be R.
Bulkiness of groups attached to the amino has great effect on the selectivity ( or β).
 substitution increases stability and selectivity but reduce activity.

22. R

23. Sympathomimetic agents
Isopreterenol (Isoprenaline):
Acts mainly on β1 and β2
More stable to MAO metabolism.
Colterol:
10X more potent on β2 than on cardiac β1

24. Sympathomimetic agents
Metaprotenol:
Selective β2 agonist.
Long acting bronchodilator (Why?)

25. Sympathomimetic agents
Albuterol
Selective β2 agonist.
Long acting bronchodilator.

26. Sympathomimetic agents
Endogenous catecholamines:
Noradrenaline, adrenaline and dopamine.
all are clinically used.
Orally inactive (Why?).
acts on D1 receptors… dilates renal blood vessels.
stimulates β1 increase cardiac output.

27. Endogenous catecholamines:
Noradrenaline (norepinephrine):
Used in hypotension resulting from surgical trauma and hemorrhage.
Orally unstable (Why?).
Given intravenously.

28. Endogenous catecholamines:
Adrenaline (epinephrine):
Not given orally.
Increases cardiac output.
Results in vasoconstriction in hemorrhage and in nasal congestion.
Stimulates β2 receptors and relax bronchial smooth muscles in asthmatic patients.

29. Sympathomimetic agents
Ephedrine:
Used as bronchodilator and cardiac stimulant.
Orally available (Why?).
Pseudoephedrine:
Used as nasal decongestant.

30. Selectivity for  versus β receptors
SAR:
N-alkyl substitution… increases potency at β and decreases potency at  receptors.
Phenol group…important for β more than  agonists.
-substitution…increases 2 selectivity.
N-alkyl extension… good for β selectivity.

31. Selectivity for  versus β receptors

32. 1-agonists Selective 1-agonists. Act as vasoconstrictors.
Used topically for nasal congestion.
Not recommended orally (Why?)

33. 2 agonists
Clonidine:
Selective 2 agonist (centrally) that lead to inhibition of sympathetic outflow from the CNS.
Used in hypertension.
Other analogues from clonidine:

34. β2-agonists
Activation of β2 receptors relaxes bronchial and uterus smooth muscles.
Adrenaline is not suitable for long term use in asthma (Why?).

35. Adrenaline use in asthma
Not recommended in Asthmatic Patients:
Non-selective, serious side effects on Cardiovascular system.
Short acting, rapidly metabolized by MAO and COMT.

36. Isopreterenol as a lead for β2-agonists
Acts mainly on β1 and β2
More stable to MAO metabolism.

37. Lead Modification
The addition of carboxylic acid in place of hydroxyl group markedly affects activity.
This might be due to the change in ionization state…. Affects the binding to receptor.

38. Lead Modification

39. Lead Modification Amide is a bioisosteric group for carboxylic acid.
Unionized at physiological pH.
Antagonist because it binds in different way to catecholamines

40. Lead Modification Soterenol has better selectivity on β2 receptors.
It binds similar to catecholamines.
More stable toward COMT and MAO enzymes

41. Lead Modification 2000 times less active on the heart.
a duration of action of 4 hours.
Is not metabolized by COMT.
R enantiomer is 68 times more active than S.
The pure R isomer has been prepared and marketed (levalbuterol)….. This is what is called chiral switching.

42. Long Acting Bronchodilators

43. Adrenergic receptors antagonists
Clinical uses:
Anti-hypertensive.
To treat cardiac failure.
To control urinary output.
In prostatic hyperplasia.

44. Adrenergic receptors antagonists
They have diverse structural features compared to catecholamines.
They will block adrenergic receptors preventing catecholamines from exerting their actions.
The binding is reversible in almost all cases.

45. Adrenergic receptors antagonists

46. -blockers
Mainly limited to selective 1 antagonists.

47. -blockers Mainly limited to selective 1 antagonists.
Used as anti-hypertensive and in benign prostatic hyperplasia.
Prazocin is short acting while terazocin and doxazocin are longer acting (Why?)

49. 2-blockers
2 receptors are presynaptic... Activation leads to decrease in N.A release.
They are used as anti-depressant agents (depression is associated with a decrease in N.A and serotonin levels).

50. Adrenergic receptors antagonists
β-blockers:
The clinically used ones are β1-blockers.
Clinical effects:
Reduce cardiac output.
Reduce rennin release from the kidney… reduce angiotensin I formation which is the precursor for angiotensin II (a potent vasoconstrictor).
Clinical uses:
in hypertension.
Angina.

51. β-blockers’ common side effects
Broncho-constriction… not recommended in asthmatic patients.
Fatigue and tiredness in limbs due to reduced cardiac output.
CNS s/e…. Mainly for lipophilic agents.

52. Adrenergic receptors antagonists
Isopreterenol was used as a lead for the synthesis of new selective β1-blockers although it is a β2-agonist.
The structure was studied to convert the agonist activity to antagonist effect.

54. Propranolol as lead for β-blockers
Substitutions lower activity
Branched alkyl groups are
Good for antagonist activity
Important for H-bonding
Important for ionic bonding
Important for H-bonding
Important for hydrophobic interactions

55. Propranolol as lead for β-blockers
Substitutions lower activity
Branched alkyl groups are
Good for antagonist activity
Important for H-bonding
Important for ionic bonding
Important for H-bonding
Important for hydrophobic interactions

56. β-BLOCKERS

57. β-BLOCKERS Amide group should be at P position for
good binding to the receptors

58. Possible Hydrophobic
interaction
Possible H-bond
interaction

59. 2nd generation β-blockers

60. 3rd generation β-blockers
Have extended alkyl side chain attached to the amino group bearing moiety capable for H-bonding.

61. An introduction to Medicinal Chemistry by Graham L. Patrick
An introduction to Medicinal Chemistry by Graham L. Patrick. 4th edition, Oxford, 2009
Wilson and Gisvolds text book of organic medicinal and pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th edition, Lippincott Williams and Wilkings 2011.
Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition, 2013.

62. The End