1. Pharmacodynamy & Receptors
Dr. M. H. Ghahremani
References:
1-B.G.Katzung; Basic & Clinical Pharmacology 2012, Chapter 2, p
2-H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2011, Chapter 1 & 2, p7-50.
3-Goodman & Gilman's: The pharmacological basis of therapeutics 2012, Chapter 3, p41-73.
Dr. Mohammad H Ghahremani

2. Pharmacodynamy:
The study of the biochemical and physiological effects of drugs and their mechanisms of action.
The objectives of the study of drug action are:
to delineate the chemical or physical interactions between drug and target cell
to characterize the sequence and scope of actions of each drug.
to understand the pathological condition and discover new targets for therapy.

3. Pharmacodynamy & Receptors
The goal of this course is to understand:
The concept of receptor
The Pharmacological effect
Drug-receptor-effect parameters
Types of receptors
Receptor signaling
Receptor regulation

4. The Receptor Concept Ehrich & Langley late 19th – early 20th century
The effects of most drugs result from their interaction with macromolecular components of the organism.
Receptor: The component of the organism (or cell) interact with the chemicals.
Receptor is a translator of hormone (or chemicals) message for the cell or organ.
Receptor : 1- binds to the hormone or drug (Ligand)
2- undergoes conformational changes
3- transduces message to the effector

5. The Receptor Concept In Receptor Concept, there is a:
Pharmacologic effect
Quantitative relationship
Selectivity

6. Pharmacologic effect Drug-receptor interaction Dose dependency
Multiple or single effect
Signal transduction and effector system
Duration of action
Regulation

7. Drug-Receptor InteractionAR
AR* R +
Response
Ligand
Receptor
Active Receptor A
Agonist BR R +
No Response
Ligand
Receptor
Inactive Receptor B
Antagonist

8. Agonist & Antagonist Antagonist is a ligand: Agonist is a ligand:
binds to a specific receptor on a specific site
in a reversible or irreversible fashion
changes receptor conformation
changes receptor to active state
produces a response
Antagonist is a ligand:
binds to a specific receptor
binds to the same or different site as agonist
in a reversible or
irreversible fashion
changes receptor conformation
changes receptor to inactive state
produces no response

9. H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.9.

10. Dose-response effect B A C % Response Log [Agonist]
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.11.
% Response
Log [Agonist] C B A

11. Potency and Efficacy
Potency is defined by the occupancy of the receptor.
A more potent ligand will occupy more receptors and produce maximum response in lower concentration
Efficacy is defined by the response elicited by the agonist
A more efficient agonist will produce higher maximum response

12. Potency and Efficiency
Response
Log [Agonist] C B A
Potency
A>B>C
Efficancy
C>A=B

13. The receptor quantification: receptor binding
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.10.

14. Competitive antagonism
pA2= -Log [KB]
= - Log 2.2x10-9
pA2=8.6
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.16.
pA2= negative Log of Antagonist results in 2 fold shift to right

15. Irreversible antagonism

16. Partial agonist; Reverse agonist
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.13.

17. Partial agonist; Reverse agonist
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.14.

18. Therapeutic Index
A=lowering BP
B=Toxicity
The therapeutic index is the ratio of the ED50 of a drug to produce a toxic effect to the ED50 to produce a therapeutic effect. For the drug example above, the ED50 for the beneficial effect of blood pressure lowering is 0.4 nM while the ED50 for toxicity is 40 nM. Therefore, the therapeutic index will be:
TI= ED50 (toxic)/ED50 (Therapeutic)
TI= 35/0.4=87.5
% Response
ED50
Log [Agonist]

19. The Receptor Types Function & coupling Location Structure
1- membrane voltage change
Ion channels
2- change in [Ca++]I
G-protein coupled
Transporter
3- Change in cAMP and IP3
4- Proliferation or Apoptosis
Tyrosine kinase
Matrix protein
Nuclear receptor
Enzymes
5-…
Structure
1- Ion channels
2- G-protein coupled
3- Tyrosine kinase
4- Matrix protein
5- Enzymes
6- Transporters
7- Nuclear receptor
Location
1- membrane bound
Ion channels
G-protein coupled
Tyrosine kinase
Matrix protein
2- Intercellular
Enzymes
cellular organelles
3- Nuclear
Transcription factor
Nuclear receptor

21. Type of Receptor-Drug interactions
Receptor: The component of the organism (or cell) interact with the chemicals.
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.23.

22. The receptor-effector linkage

23. The Receptor Types
H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, p.27.

24. Ion Channels Gating Voltage gating Ligand gating
Multiple subunits making a pore in the middle
In ligand gated two similar subunit
 Ligand binding
Flow of the current
Inward or outward current of ions
Type of Ions
Na+, K+, Ca++, Cl-

25. Ion Channels Ligand gated : nicotinic receptor, GABA receptor
Voltage gated:
Calcium channels ( N, L,T, P type);
Sodium channels;
Potassium channels (inward rectifier)

26. Ligand Gated Ion Channel

27. Glutamate receptor
Domain structure in glutamate receptor ion channels.
Each subunit consists of a bilobed amino-terminal domain (NTD), the two-domain ligand-binding core (D1 D2), an ion channel with three membrane-spanning segments (1–3) and a pore loop (P), and a cytoplasmic domain of variable length.
Mayer, Current Opinion in Neurobiology 15, 2005,

28. Voltage sensor
Segments S1–S4 : S1, white; S2, pink; S3, red; S4, light blue; S5–S6 pore region, green.
(a) The paddle model as presented by Jiang et al. [9]. In this model the S1 and S2 segments are embedded in the bilayer and the S4 charges (dark blue circles) are pointing into the bilayer. (b) Topology as proposed by Cuello et al. [8]. S1 and S2 segments are transmembrane and S1 is surrounded by the rest of the protein. The S4 segment is located in the periphery but its charges are pointing away from the bilayer and into the protein core, with the most extracellular charge exposed to the transition region of the lipid bilayer. Because most of the charges are covered by the S4 segment, only the first and fourth charges are shown.

29. G protein coupled receptor
N-Terminal II
III IV I V VI
VII
C-Terminal C1 C2 C3

30. G protein coupled receptor
Seven transmembrane domain; Intracellular and extracellular loops
Couples to G protein (α and  subunit)
Active receptor activates G protein and dissociates α subunit from  subunit
GPCR couples to multiple effectors
Inactivation of G protein changes the receptor into inactive state

32. G protein cycle AC
PLC
Ligand bg
GTP a + bg a
GDP a
GDP

33.  subunit:  Subunits 23 distinct subtype Divided into 4 family
1-Gs consists of s and olf
2-Gi consists of i, o, t and z
3-Gq consists of q, 11/14 and 15/16
4-G12/13 consists of 12 and 13
GTPase domain
One large  helix
 Subunits
Functionally one subunit
Six  subunits and 12  subunits
1  1 and 2
2  2 but not 1

34. N-Terminal II
III IV I V VI
VII
C-Terminal C1 C2 C3

35. GPCR Baldwin model (Top View)
Inactive state
Active state
Current Opinion in Cell Biology 1997, 9:134–142

36. THE JOURNAL OF BIOLOGICAL CHEMISTRY.
Vol. 273, (2), pp. 669–672, 1998

37. G protein coupling Gαs couples to AC and  cAMP
Gαs can be activated by cholera toxin (CTX)
2-adrenergic, D1 dopaminergic, PGE2 receptor
Gαi couples to AC and  cAMP
Gαi can be inhibited by pertussis toxin (PTX)
2-adrenergic, M2 muscarinic, 5-HT1 serotonergic
Gαo couples to K+ channel and hyperpolarizes the cell
Gαo can be inhibited by pertussis toxin (PTX)
M2 muscarinic, 5-HT1 serotonergic

38. G protein coupling Gαt couples to Ca++ channels and closes the channel
Retinal receptors
Gαq couples to PLC and  DAG and Ca++
M1 muscarinic, 5-HT2 serotonergic
G couples to PLC, AC2,6, IRK channel and PI3Kinase

40. Pharmacodynamy & Receptors
Dr. M. H. Ghahremani
References:
1-B.G.Katzung; Basic & Clinical Pharmacology 2001, Chapter 2, p 9-34.
2-H.P. Rang, M.M. Dale & J.M. Ritter, Pharmacology 2003, Chapter 1 & 2, p7-50.
3-Goodman & Gilman's: The pharmacological basis of therapeutics 2006, Chapter 1, p1-40.
Dr. Mohammad H Ghahremani

41. Receptor Protein-Tyrosine Kinases
Figures_Hi-res\ch13\cell3e13130.jpg

42. Tyrosine kinase receptor
Figures_Hi-res\ch13\cell3e13140.jpg
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases

43. Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Figures_Hi-res\ch13\cell3e13150.jpg

44. Ras Activation Downstream of Receptor Protein-Tyrosine Kinases
Figures_Hi-res\ch13\cell3e13340.jpg

45. Activation of the ERK/MAPKinases
Figures_Hi-res\ch13\cell3e13320.jpg

46. Tyrosine kinase receptor Signaling
These receptors directly link to their intracellular enzyme targets
Commonly associated with polypeptide growth and differentiation signals.
The basic structure consists of an N-terminal ligand binding domain, a single transmembrane α helix and a cytosolic C-terminal domain that has the protein-tyrosine kinase activity.
Can be a monomer or a dimer
Following ligand binding these receptors form dimers and then autophosphorylate at tyrosine residues in the C-terminus
The phosphorylation stimulates the kinase activity of the receptor and creates binding site for additional intracellular signals
They can then activate target molecules through kinase activity or protein binding and subsequent activation

47. Signaling from Cytokine Receptors
Figures_Hi-res\ch13\cell3e13171.jpg

48. Tyrosine kinase receptor Signaling

49. Nuclear Receptors Ligand easily passes the membrane
A ligand binding and a DNA binding domain
Activates transcription :Directly or indirectly
Gene activation is dependent on the cell type
Thyroid receptor, Steroid receptor, Vitamin D

50. Estrogen Action
Figures_Hi-res\ch13\cell3e13030.jpg

51. Gene Regulation by the Thyroid Hormone Receptor
Figures_Hi-res\ch13\cell3e13040.jpg

52. Nuclear Receptor Superfamily
Steroid Hormones and
Nuclear Receptor Superfamily
The signaling molecules (Ligand) can pass through the cell membrane and bind intracellular receptors; example: the steroid hormones (estrogen, testosterone, progesterone, the corticosteroids and ecdysone) as well as thyroid hormone, vitamin D3 and retinoic acid
once in the cell steroid hormones bind proteins that are part of the nuclear receptor superfamily which act as transcription factors
The receptors contains ligand binding domain, DNA binding domain and transcriptional regulation domain
The signaling directly regulates gene expression