Medicinal chemistry for the students perusing master in chemistry

concept of pharmacodynamics in medicinal chemistry

1. Pharmacodynamics

2. Site of
Action
Dosage Effects
Plasma
Concen.
PharmacokineticsPharmacodynamics

3. Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”
TISSUE
RESERVOIRS
SYSTEMIC
CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION

4. AIDS MEMORIZATION OF:

5. WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
• Better assessment of new modalities for using drugs
• Better assessment of new indications for drugs
• Better assessment of new concerns regarding risk-benefit
AIDS EVALUATION OF MEDICAL LITERATURE:

6. WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
The patient has more respect for and trust in a therapist who
can convey to the patient how the drug is affecting the
patient’s body.
AIDS PATIENT-DOCTOR RELATIONSHIP:
A patient who understands his/her therapy is more inclined
to become an active participant in the management
of the patient’s disease.

7. WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
Knowledge of how a drug works increases the therapist’s
confidence that the drug is being used appropriately.
PEACE OF MIND!

8. HOW DO DRUGS WORK?
• Some antagonize, block or inhibit endogenous proteins
• Some activate endogenous proteins
• A few have unconventional mechanisms of action

9. HOW DO DRUGS ANTAGONIZE, BLOCK OR
INHIBIT ENDOGENOUS PROTEINS?
• Antagonists of Cell Surface Receptors
• Antagonists of Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
•Inhibitors of Signal Transduction Proteins

10. A macromolecular component of the organism that
binds the drug and initiates its effect.
Definition of RECEPTOR:
Most receptors are proteins that have undergone various
post-translational modifications such as covalent
attachments of carbohydrate, lipid and phosphate.

11. A receptor that is embedded in the cell membrane and functions
to receive chemical information from the extracellular
compartment and to transmit that information to
the intracellular compartment.
Definition of CELL SURFACE RECEPTOR:

12. HOW DO DRUGS WORK BY
ANTAGONIZING CELL SURFACE RECEPTORS?
KEY CONCEPTS:
• Cell surface receptors exist to transmit chemical signals from
the outside to the inside of the cell.
• Some compounds bind to cell surface receptors, yet do not
activate the receptors to trigger a response.
• When cell surface receptors bind the molecule,
the endogenous chemical cannot bind to the
receptor and cannot trigger a response.
• The compound is said to “antagonize” or “block” the receptor
and is referred to as a receptor antagonist.

13. HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Cell Membrane
Unbound Endogenous Activator (Agonist) of Receptor
Inactive Cell Surface Receptor
Extracellular
Compartment
Intracellular
Compartment

14. HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Cell Membrane
Bound Endogenous Activator (Agonist) of Receptor
Active Cell Surface Receptor
Extracellular
Compartment
Intracellular
Compartment
Cellular Response

15. HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Cell Membrane
Displaced Endogenous Activator (Agonist) of Receptor
Inactive Cell Surface Receptor Upon being Bound
Extracellular
Compartment
Intracellular
Compartment
Bound Antagonist of Receptor (Drug)

16. Footnote:
Most antagonists attach to binding site on receptor for
endogenous agonist and sterically prevent
endogenous agonist from binding.
If binding is reversible - Competitive antagonists
If binding is irreversible - Noncompetitive antagonists

However, antagonists may bind to remote site on receptor and
cause allosteric effects that displace endogenous agonist
or prevent endogenous agonist from
activating receptor. (Noncompetitive antagonists)
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

17. HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Cell Membrane
Displaced Endogenous Activator (Agonist) of Receptor
Inactive Receptor
Extracellular
Compartment
Intracellular
Compartment
Bound Antagonist of Receptor
Allosteric Inhibitor
Active Receptor

18. ARE DRUGS THAT ANTAGONIZE CELL
SURFACE RECEPTORS CLINICALLY
USEFUL?
• Angiotensin Receptor Blockers (ARBs) for high blood pressure,
heart failure, chronic renal insufficiency
(losartan [Cozaar
®
]; valsartan [Diovan
®
])
Some important examples:
• Beta-Adrenoceptor Blockers for angina, myocardial infarction,
heart failure, high blood pressure, performance anxiety
(propranolol [Inderal
®
]; atenolol [Tenormin
®
])

19. HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?
Unbound Endogenous Activator
(Agonist) of Nuclear Receptor
Inactive Nuclear Receptor
in cytosolic compartment
Intracellular
Compartment
Nucleus
DNA
Inactive Nuclear Receptor
in nuclear compartment

20. HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?
Intracellular
Compartment
Nucleus
DNA
Modulation of
Transcription
Active Nuclear Receptor
Bound Endogenous Activator
(Agonist) of Nuclear Receptor

21. HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?
Displaced Endogenous Activator
(Agonist) of Nuclear Receptor
Intracellular
Compartment
Nucleus
DNA
Bound Antagonist
of Receptor (Drug)
Inactive Nuclear Receptor
In Cytosolic Compartment
Inactive Nuclear Receptor
In Nuclear Compartment

22. ARE DRUGS THAT ANTAGONIZE NUCLEAR
RECEPTORS CLINICALLY USEFUL?
• Mineralocorticoid Receptor Antagonists for edema due to
liver cirrhosis and for heart failure
(spironolactone [Aldactone
®
])
Some important examples:
• Estrogen Receptor Antagonists for the prevention and
treatment of breast cancer (tamoxifen [Nolvadex
®
])

23. HOW DO DRUGS ANTAGONIZE, BLOCK OR
INHIBIT ENDOGENOUS PROTEINS?
• Antagonists of Cell Surface Receptors
• Antagonists of Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
•Inhibitors of Signal Transduction Proteins

24. HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate Product
Cellular Function
Inactive Enzyme
Substrate
Bound Enzyme
Inhibitor (Drug)

25. HOW DO DRUGS WORK BY
INHIBITING ENZYMES?
KEY CONCEPTS:
• Enzymes catalyze the biosynthesis of products from substrates.
• Some drugs bind to enzymes and inhibit enzymatic activity.
• Loss of product due to enzyme inhibition mediates the
effects of enzyme inhibitors.

26. ARE DRUGS THAT INHIBIT ENZYMES
CLINICALLY USEFUL?
• Cyclooxygenase Inhibitors for pain relief,
particularly due to arthritis (aspirin; ibuprofen [Motrin
®
])
Some important examples:
• Angiotensin Converting Enzyme (ACE) Inhibitors for
high blood pressure, heart failure, and
chronic renal insufficiency
(captopril [Capoten
®
]; ramipril [Altace
®
])
• HMG-CoA Reductase Inhibitors for hypercholesterolemia
(atorvastatin [Lipitor
®
]; pravastatin [Pravachol
®
])

27. HOW DO DRUGS ANTAGONIZE, BLOCK OR
INHIBIT ENDOGENOUS PROTEINS?
• Antagonists of Cell Surface Receptors
• Antagonists of Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
•Inhibitors of Signal Transduction Proteins

28. ARE DRUGS THAT BLOCK ION
CHANNELS CLINICALLY USEFUL?
• Calcium Channel Blockers (CCBs) for angina and high blood
pressure
(amlodipine [Norvasc
®
]; diltiazem [Cardizem
®
])
Some important examples:
• Sodium Channel Blockers to suppress cardiac
arrhythmias
(lidocaine [Xylocaine
®
]; amiodarone [Cordarone
®
])

29. ARE DRUGS THAT INHIBIT TRANSPORTERS
CLINICALLY USEFUL?
• Selective Serotonin Reuptake Inhibitors (SSRIs) for the
treatment of depression
(fluoxetine [Prozac
®
]; fluvoxamine [Luvox
®
])
Some important examples:
• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in
renal epithelial cells to increase urine and sodium
output for the treatment of edema
(furosemide [Lasix
®
]; bumetanide [Bumex
®
])

30. • Tyrosine Kinase Inhibitors for chronic myelocytic leukemia
(imatinib [Gleevec
®
])
Some important examples:
• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction
(sildenafil [Viagra
®
])
• This is a major focus of drug development
ARE DRUGS THAT INHIBIT SIGNAL
TRANSDUCTION PROTEINS
CLINICALLY USEFUL?

31. HOW DO DRUGS WORK BY ACTIVATING
ENDOGENOUS PROTEINS?
• Agonists of Cell Surface Receptors
(e.g. alpha-agonists, morphine agonists)
• Agonists of Nuclear Receptors
(e.g. HRT for menopause, steroids for inflammation)
• Enzyme Activators
(e.g. nitroglycerine (guanylyl cyclase), pralidoxime)
• Ion Channel Openers
(e.g. minoxidil (K) and alprazolam (Cl))

32. HOW DO CHEMICALS WORK BY ACTIVATING
CELL SURFACE RECEPTORS?
KEY CONCEPTS:
•Cell surface receptors exist to transmit chemical signals from
the outside to the inside of the cell.
• Some chemicals bind to cell surface receptors and
trigger a response.
• Chemicals in this group are called receptor agonists.
• Some agonists are actually the endogenous chemical signal,
whereas other agonists mimic endogenous chemical signals.

33. HOW DO CHEMICALS WORK BY
UNCONVENTIONAL MECHANISMS OF ACTION?
•Disrupting of Structural Proteins
e.g. vinca alkaloids for cancer, colchicine for gout
• Being Enzymes
e.g. streptokinase for thrombolysis
• Covalently Linking to Macromolecules
e.g. cyclophosphamide for cancer
• Reacting Chemically with Small Molecules
e.g. antacids for increased acidity
• Binding Free Molecules or Atoms
e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

34. HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION (Continued)?
•Being Nutrients
e.g. vitamins, minerals
• Exerting Actions Due to Physical Properties
e.g. mannitol (osmotic diuretic), laxatives
• Working Via an Antisense Action
e.g. fomivirsen for CMV retininitis in AIDS
• Being Antigens
e.g. vaccines
•Having Unknown Mechanisms of Action
e.g. general anesthetics

35. Characteristics of Drug-Receptor Interactions
•Chemical Bond: ionic, hydrogen,
hydrophobic, Van der Waals, and covalent.
•Saturable
•Competitive
•Specific and Selective
•Structure-activity relationships
•Transduction mechanisms

37. NH
4
+
-CH
2(n)-NH
4
+

38. Receptor Transduction Mechanisms
•Ion channel linked receptors e.g. Ach nicotinic
(Na
+
) and GABA (Cl
-
)
•Second messenger generation,
adenylate cyclase stimulation or inhibition - cAMP,
guanylate cyclase - cGMP,
phospholipase C - IP3, DAG
•Some receptors are themselves protein kinases
•Intracellular receptors (e.g. corticosteroids, thyroid
hormone)

39. k1
D + R DR
k2
By Law of Mass Action: [D]•[R]•K
1
= [DR]•K
2
Therefore K
2
/K
1
= [D]•[R]/[DR] = K
d

If R
T = total # of receptors, then
R
T = [R] + [DR]
Replace [R] by (R
T
-[DR]) and rearrange:
[DR] [D]
RT Kd + [D]
=
OCCUPATION THEORY OF DRUG-RECEPTOR
INTERACTIONS
EFFECT
effect
Max. effect
=

40. K
d
effect [DR] [D]

Max. effectRT Kd + [D]
==
When [D] = K
d
[DR]
R
T
= 0.5
[D]
[
D
R
]
/
R
T
0 5 10 15 20
0.00
0.25
0.50
0.75
1.00

42. Receptor Binding
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th
ed., New York: McGraw-Hill, 1996).
%
B
o
u
n
d
Concentration of Ligand
K
d

43. [D]
[
D
R
]
/
R
T
0.01 0.10 1.00 10.00 100.00
0.00
0.25
0.50
0.75
1.00
Kd=1
kd=5
Kd=0.5
Compounds Have Different Affinities for the Same Receptor

44. Competitive Noncompetitive
Types of Receptor Antagonists

46. [D](concentration units)
%

M
a
x
im
a
l
E
f
f
e
c
t
0.01 0.10 1.00 10.00 100.00 1000.00
0.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist
PARTIAL AGONISTS - EFFICACY
Even though drugs may occupy the same # of receptors, the
magnitude of their effects may differ.

48. Drug (D)
Ri
DRi DRa
Ra
CONFORMATIONAL SELECTION
HOW TO EXPLAIN EFFICACY?
The relative affinity
of the drug to either
conformation will
determine the effect of
the drug

49. R
R
1
*
R
2
*
R
3
*
R
R
R
1
*
R
1
*
R
2
*
R
2
*
R
3
*
R
3
*
From Kenakin, T. Receptor conformational induction versus selection: all part of the same energy
landscape. TiPS 1996;17:190-191.

50. Spare Receptors

51. Receptor Regulation
•Sensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
2. Inhibition of synthesis or release of
hormone/neurotransmitter - Denervation
•Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
Homologous vs. Heterologous
Uncoupling vs. Decreased Numbers

54. From Nies A and Speilberg SP. Principles of Therapeutics. in Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 9
th
edition, 1996. Pages 43-62.McGraw Hill,

55. GRADED DOSE-
RESPONSE CURVE
ED50
ED50

56. QUANTAL DOSE-
RESPONSE CURVE
Frequency
Distribution
Cumulative
Frequency
Distribution

58. Morphine
Aspirin

59. THERAPEUTIC INDEX – AN INDEX OF SAFETY
Hypnosis Death

60. Margin of Safety =
LD
1
ED
99
ED
50
A
ED
99
A
LD
1A

61. Causes of Variability in Drug Response
Those related to the biological system
1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health
5. Placebo effect

62. Causes of Variability in Drug Response
•Those related to the conditions of administration
1. Dose, formulation, route of administration.
2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug allergy
3. Drug interactions:
chemical or physical;
GI absorption;
protein binding/distribution;
metabolism (stimulation/inhibition);
excretion (pH/transport processes);
receptor (potentiation/antagonism);
changes in pH or electrolytes.