The document discusses the biochemistry and physiology of the sympathetic nervous system, focusing on adrenergic receptors and their agonists and antagonists. It covers the mechanisms of action, structural differences, and clinical applications of various catecholamines and sympathomimetics. Additionally, the document highlights the significance of receptor selectivity in drug design and therapeutic use, particularly in managing diseases like hypertension and asthma.

1. Dr. Bilal Al-Jaidi
Assistant Professor in Medicinal Chemistry and Drug Design
Faculty of Pharmacy, Philadelphia University-Jordan
Email: bjaidi@philadelphia.edu.jo

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.  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. 1. receptors.
 1 : in bronchial smooth muscles, GIT, liver and veins.
 2 : in GIT
2. 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 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.

11.  At physiological pH, more than 95% ionized.
 Chemically unstable

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

13. NE
Reuptake

14.  MAO (Monoamine oxidase):

15.  COMT (Catecholamine O-methyl transferase):

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

17. Affecting Noradrenaline release
Affecting Noradrenaline storage
Affecting Noradrenaline interaction with receptors
Affecting Noradrenaline reuptake
Affecting MAO or COMT
Affecting Noradrenaline synthesis

18.  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 catecholamine storage:
 Inhibits transporter protein of noradrenaline to be
stored in the storage vesicles.
 Used in hypertension.

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

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

25. Albuterol
 Selective β2 agonist.
 Long acting bronchodilator.

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

28.  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.  Ephedrine:
 Used as bronchodilator and cardiac stimulant.
 Orally available (Why?).
 Pseudoephedrine:
 Used as nasal decongestant.

30.  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. β selectivity
selectivity
β selectivity

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

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

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

35. 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.  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.

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

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

41.  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.

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

44.  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.

46.  Mainly limited to selective 1 antagonists.

47.  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 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.  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.  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.  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. Branched alkyl groups are
Good for antagonist activity
Important for ionic bonding
Important for H-bonding
Substitutions lower activity
Important for H-bonding
Important for hydrophobic interactions

55. Branched alkyl groups are
Good for antagonist activity
Important for ionic bonding
Important for H-bonding
Substitutions lower activity
Important for H-bonding
Important for hydrophobic interactions

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

58. Possible Hydrophobic
interaction
Possible H-bond
interaction

60.  Have extended alkyl side chain attached to the amino
group bearing moiety capable for H-bonding.

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2. Wilson and Gisvolds text book of organic medicinal and
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3. 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