Medicinal Chemistry/ CHEM

458/658
Chapter 8- Receptors and
Messengers
Bela Torok
Department of Chemistry
University of Massachusetts Boston
Boston, MA

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 Introduction

• Receptor – specific areas of proteins

- embedded in the cell membrane
- nucleus

ligand (endogenous/exogenous) and binding domain,

biological response

secondary messengers, possibility of intervention

signal transduction

2
 Introduction

• secondary messengers, possibility of intervention

agonists and antagonists (several groups of xenobiotics, not just
drugs)

3
 The Chemistry of the Ligand-Receptor Binding

• Full spectrum of chemical bonding

ligand to receptor – diffusion or transport proteins

4
 The Chemistry of the Ligand-Receptor Binding

• Full spectrum of chemical bonding

- charge-transfer complexes

- hydrophobic bonding and London dispersion forces

5
 Structure and Classification of Receptors

• Family 1

- endogenous ligand: fast neurotransmitters

- nAChR, GABAA or glutamate receptors)
- general structure

Four/five subunits
with total of 16-20
membrane-spanning
domains.

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 Structure and Classification of Receptors

• Family 2

- endogenous ligand: hormones and slow transmitters

- mAChR and noradrenergic receptors ( it is coupled to the effector
system by G-protein)
- general structure

7
 Structure and Classification of Receptors

• Family 3

- endogenous ligand: insulin and growth factors

- insulin receptors ( it is linked to tyrosine kinase)
- general structure

8
 Structure and Classification of Receptors

• Family 4

- endogenous ligand: steroid hormones, thyroid hormones,

vitamins (D), retinoic acid
- antidiuretic hormone (ADH) or vasopressing receptors
- general structure

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 Structure and Classification of Receptors

• Further classification

- e.g. mAChR or nAChR , even further m1AChR – m5AChR

- α or β adrenoreceptors

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 General Mode of Operation
• Ligands activate or deactivate (inhibit) – primary messengers
- primary messengers: hormones, neurotransmitters other
endogenous substances, or xenobiotics (drugs, bacteria, virus)
Hormones:

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autocoids
 General Mode of Operation
• Ligands activate or deactivate (inhibit) – primary messengers
- primary messengers: hormones, neurotransmitters other
endogenous substances, or xenobiotics (drugs, bacteria, virus)
Neurotransmitters:

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 General Mode of Operation
• Mode of action:
Superfamily 1/2

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 General Mode of Operation
• Superfamily 1 – ion channel control

e.g. nAChR

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 General Mode of Operation
• Superfamily 2 – most receptors have one polypeptide chain

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 General Mode of Operation

• Superfamily 2 – role of G proteins

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 General Mode of Operation

• Superfamily 2 – role of G proteins

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 General Mode of Operation

• Superfamily 2 – role of G proteins

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 General Mode of Operation

• Superfamily 3

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 General Mode of Operation

• Superfamily 4

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 Ligand-Response Relationships

• L – R binding loss of energy (affinity)

L R L + R L + R L R

L R L R
KD = Ka =
L R L R

pD2 = - log K D = - log EC50

21
 Ligand-Response Relationships

• Experimental Determination of L-R curves

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 Ligand-Response Relationships

• Experimental Determination of L-R curves

23
 Ligand-Response Relationships
• Agonist Concentration-Response Relationships

24
 Ligand-Response Relationships
• Antagonist Concentration-Response Relationships

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 Ligand-Response Relationships
• Antagonist Concentration-Response Relationships

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 Ligand-Response Relationships
• Antagonist Concentration-Response Relationships

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 Ligand-Response Relationships

• Partial Agonists – act both ways

- multiple pharmacophores that act differently

- reasonable but not perfect fits

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 Ligand-Response Relationships
• Desensitization

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 Ligand-Receptor Theories
• Clark’s occupancy theory
E [ DR ] [D]
Emax = = K D = EC50
[RT] K D + [D]

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 Ligand-Receptor Theories
• Clark’s occupancy theory

new developments:
- many D-R complex formations are not reversible
- the R sites are not always independent
- not every D-R formation is bimolecular
- max response maybe obtained before every R is occupied
- the response is not linear to the proportions of receptors occupied

• Ariens and Stephenson (1950s) – intrinsic activity/efficacy

E max of a drug
=
E max of the most active agonist in the same structural series

E [ DR ] [D]
Emax = =
[RT] K D + [D] 31
 Ligand-Receptor Theories
• The Rate Theory (Paton, 1961)
- stimulation only when the ligand first occupies the receptor
- second conformational change – more stable complex
- when ligand leaves further stimulus can occur
- type of activity is independent of the number of receptors, it
depends on the rate of binding/release

correlation : poor

• The Two-State Model

- receptors exist in an active/inactive state (relaxed/R, tensed/T)
- equilibrium between the two states

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 Drug Action and Design
• Agonists

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 Drug Action and Design
• Agonists

24X activity

400X activity
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 Drug Action and Design
• Antagonists

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 Drug Action and Design
• Case study 1 – CNS drugs
citalopram – antagonist antidepressant

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 Drug Action and Design
• Case study 1 – CNS drugs
citalopram – antagonist antidepressant

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 Drug Action and Design
• Case study 1 – CNS drugs
citalopram

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 Drug Action and Design
• Case study 2 – β blockers (β adrenoreceptor antagonists in the heart)

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 Drug Action and Design
• Case study 2 – β blockers (β adrenoreceptor antagonists in the heart)
1 1 2

vasodilation decreases heart rate bronchocontsriction

decreases blood glucose level decreases blood pressure decreases blood glucose

pupil constriction increase in gut secretions

and motility

causes impotence

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 Drug Action and Design
• Case study 2 – selective β blockers (β adrenoreceptor antagonists in
the heart)

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