This presentation includes the mechanism behind various drug receptors as well as receptor regulation

1. Drug Receptor Interactions
Dr. Shruthi Rammohan

2. Overview:
• History
• Theories
• Definitions
• Types of Receptors
• Receptor Regulation
• Applied Pharmacology

3. What is a Receptor
• Receptor- a binding site located on the
surface/inside the effector cell that
serves to recognize the signal
molecule/drug and initiate the response
to it, but has no other function itself

4. A Brief History…
Paul Ehrlich
(1854-1915)
John Newport Langley
(1852-1925)

5. John Henry Gaddum
(1900-1965)
Alfred Joseph Clark
(1885-1941)
Raymond P. Ahlquist
(1914–1983)

6. Drug-Receptor Theories
• Hypothesis of Clark
“ The Pharmacologic effect of the drug depends on
the percentage of the receptors occupied”
If receptors are occupied, maximum effect is obtained.
It is also called as the Occupation Theory

7. Drug-Receptor Theories
• Hypothesis of Ariens and Stephenson
“ Effectiveness of a drug lasts as long as the
receptor is occupied.”
-Intensity of effect is directly proportional to the number
of receptors occupied

8. Drug-Receptor Theories
• Hypothesis of Paton
“ Effectiveness of a drug does not depend on the
actual occupation of the receptor but by obtaining
proper stimulus”
-Response is proportional to the rate of Drug-Receptor
Complex formation
-Duration of receptor occupation determines if a
drug is an agonist, partial agonist, or antagonist
This is also known as the Rate Theory

9. Drug-Receptor Theories
• Lock and Key Hypothesis
“ The drug molecule must fit into the receptor AND
produce its action like a key fits into the lock AND
opens it also”
This is known as Intrinsic Activity

10. Terminology
Receptor- a binding site located on the surface/inside
the effector cell that serves to recognize the
signal molecule/drug and initiate the response
to it, but has no other function itself
Efficacy- potential maximum therapeutic response
that a drug can produce
Potency- amount of drug needed to produce an effect
Ligand- a molecule which binds selectively to a
receptor or site
Affinity- the ability to bind with the receptor

11. Terminology
Agonist- activates a receptor to produce an effect similar to
that of the physiological signal molecule
Partial activates a receptor to produce a submaximal effect
Agonist- but antagonizes the action of a full agonist
Inverse activates a receptor to produce an effect in the
Agonist- opposite direction to that of the agonist
Antagonist- prevents the action of an agonist on a receptor or the
subsequent response but does not have an effect of its own

13. Terminology
Competitive
Antagonism
Non-competitive
Antagonism
Reversible Irreversible
• Same receptor
• Weak bonds
• ↑ agonist
overcomes effect
of antagonist
• Parallel right
shift of DRC
• Same receptor
sites
• Strong bonds
• ↑ agonist does not
overcome effect of
antagonist
• Reduced efficacy
and unaltered
potency
• Binds to another site other
than agonist
• Prevents receptor activation
by agonist

15. Agonist + Antagonist
Agonist alone
Antagonist alone
Noncompetitive Antagonist
Agonist or Antagonist Concentration
%
R
e
s
p
o
n
s
e

16. Two State Receptor Model
Ri Ra
AGONIST
PARTIAL
AGONIST
INVERSE
AGONIST
ANTAGONIST
RESTING EQUILLIBRIUM

17. Types of Receptors
• Ligand Gated Ion Channels
• G- Protein Coupled Receptors
• Kinase Linked Receptors
• Nuclear Receptors

18. Ligand Gated Ion Channel
• Ligand ( ) binds to
receptor site
• Channel will open ( )
or close ( )
• Ions ( ) will enter/exit the
cell depolarization or
hyperpolarization
EFFECT

19. Ligand Gated Ion Channel
Ion Channel Receptor Neurotransmitter Drugs
Agonist/Antagonist
GABA Receptors GABA Benzodiazepines
Flumazenil
Glycine Receptors Glycine Taurine
Strychnine
Glutamate Receptors Glutamate NMDA
Ketamine
Nicotinic ACh Receptors Acetylcholine Nicotine
Tubocurarine
5 HT3 Receptors Serotonin Quipazine
Ondansetron

20. G-Protein Coupled Receptors
• Structure
α β
γ
• Amino terminus
• Carboxylic acid
terminus
• Extracellular Loop
• Intracellular Loop
• Transmembrane
Domain
G-protein
GDP

21. G-Protein Coupled Receptors
α β
γ
GDP
GTP
Ligand
Ligand binds to GPCR
-GDP exchanged for GTP
-α-subunit dissociates

22. G-Protein Coupled Receptor
α
GTP
Effector
Protein
-Effector protein
activated
- Effect brought about by
signaling 2nd messenger

23. Receptor Signaling Pathways
Effector Protein Second Messenger
• Adenylyl Cyclase (AC)
• Activation
• Inhibition
• Phospholipase C (PLC)
• cAMP
• DAG and IP₃

24. Adenylyl Cyclase Pathway

26. TYPES EFFECTOR PATHWAY RECEPTOR DRUGS
Agonist/Antagonist
Gs
Adenylyl Cyclase
- Activation
- Ca2+ channel opening
Β- adrenergic
Dopamine- D1
Salbutamol/Propanolol
Fenoldopam/Ecopipam
Gi
Adenylyl Cyclase
- Inhibition
- K+ channel opening
M2
Dopamine- D2
GABAB
α2- adrenergic
Serotonin 5-HT1
Methacholine/Atropine
Cabergoline/Haloperidol
Baclofen
Clonidine/Yohimbine
Buspirone/Lecozotan
Go
Channel Regulation
- K+ channel opening
M2
Dopamine- D2
GABAB
α2- adrenergic
Serotonin 5-HT1
“
Gq
Phospholipase C
- Activation
M1 M3
α1- adrenergic
Serotonin 5-HT2
Bethanechol/Pirenzepine
Phenylephrine/Prazosin
Methysergide/Trazodone

27. Enzyme Linked Receptors
• Structure
t t
• Binding site
• Receptor tyrosine
kinase (RTKs)
• Catalytic sites
• Tyrosine residues

28. Enzyme Linked Receptor
• Ligand Examples:
- Insulin
- Epidermal Growth Factor

29. Enzyme Linked Receptors
Ligand
t t
2 ATP
2 ADP
p p
p
• Ligand binds to receptor
site
• Receptor is activated
dimerization occurs
• Phosphorylation
• Activation of RTK
• Phosphorylated SH2 proteins
bind to receptor
• Intracellular signalling
protein
• Cellular response

30. Enzyme Linked Receptor

31. JAK-STAT- Kinase Binding Receptors
• Ligand binds to receptor
• Induces receptor dimerization
• Activates intracellular domain to
bind to Janus Kinase protein
• Phosphorylation
• Signals and binds to STAT protein
• Phosphorylation of tyrosine
residues on STAT
• Dimerization of STAT
• Dissociation of STAT from receptor
• STAT transferred to nucleus
• Transcription and Translation
Effect

32. Jak-STAT Receptor
• Ligand Examples:
- Cytokines
- Interferons

33. Nuclear Receptors
Cytoplasm
NH2-
• Amino terminus
• Carboxylic acid
terminus
• HSP90
• DNA binding domain
with Zinc Fingers
• Structure
Nucleus
-COOH

34. Nuclear Receptors
• Ligand Examples:
- Steroid Hormones
- Thyroxine
- Vitamin D
- Vitamin A

35. Nuclear Receptors
Cytoplasm
DNA
mRNA
Transcription
Ribosome
Protein
EFFECT
Steroid Hormone

36. Regulation of Receptors
Response Response
• DOWN REGULATION
• DESENSITISATION
• UP REGULATION
• SUPERSENSITIVITY

37. Regulation of Receptors
DOWN REGULATION UP REGULATION
• Prolonged use of agonist • Prolonged use of antagonist
in receptor number and
receptor sensitivity
Drug effect
in receptor number and
receptor sensitivity
Drug effect

38. Regulation of Receptors
DESENSITISATION SUPERSENSITIVITY
• When initial high response
is reached, the effect
diminishes within
seconds/minutes even in the
continued presence of the
agonist
• Reversible
• exaggerated response
• prolonged block by an
antagonist causing fast up
regulation of receptors
• new receptors are highly
sensitive!
• Tardive dyskinesia with
Neuroleptics

39. Regulation of Receptors

40. Importance of Knowing Receptors
Receptor Related Diseases
Ion Channels
• Myasthenia Gravis- nicotinic cholinergic receptors
Enzyme- Linked Receptors
• Insulin Resistant Diabetes- insulin receptors
Nuclear Receptors
• Grave’s Disease- TSH receptors
• Male Pseudohermaphroditism- LH receptors
• Familial hypercholesterolemia- LDL receptors
• Congenital Night Blindeness- rhodopsin receptors
• Central Hypogonadism- GnRH receptors
GPCR
• Extreme Obesity- Melanocortin receptor

41. References
• Essentials of Medical Pharmacology, 7th Edition. KD
Tripathi
• Principles of Pharmacology, 2nd Edition. HL Sharma,
KK Sharma
• Rang & Dale’s Pharmacology, 8th Edition. HP Rang,
JM Ritter, RJ Flower, G Henderson
• Basic and Clinical Pharmacology, 13th Edition. BG
Katsung, AJ Trevor
• Maehle AH. A binding question: the evolution of the
receptor concept. Endeavour. 2009;33(4):135-140.

42. Thank You