Medicinal Chemistry/ CHEM 458/658

Chapter 8- Receptors and Messengers

Bela TorokDepartment 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

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3

Introduction

• secondary messengers, possibility of intervention

agonists and antagonists (several groups of xenobiotics, not justdrugs)

• Full spectrum of chemical bonding

ligand to receptor – diffusion or transport proteins

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The Chemistry of the Ligand-Receptor Binding

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The Chemistry of the Ligand-Receptor Binding

• Full spectrum of chemical bonding- charge-transfer complexes

- hydrophobic bonding and London dispersion forces

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Structure and Classification of Receptors

• Family 1

- endogenous ligand: fast neurotransmitters- nAChR, GABAA or glutamate receptors)- general structure

Four/five subunitswith total of 16-20membrane-spanningdomains.

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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 effectorsystem by G-protein)

- general structure

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Structure and Classification of Receptors

• Family 3

- endogenous ligand: insulin and growth factors- insulin receptors ( it is linked to tyrosine kinase)- general structure

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

Hormones:

General Mode of Operation

autocoids

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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)

Neurotransmitters:

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General Mode of Operation

• Mode of action:Superfamily 1/2

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• Superfamily 1 – ion channel control

e.g. nAChR

General Mode of Operation

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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

KD =L R

L R

pD2 = - log KD = - log EC50

L + R L R

Ka =L R

L R

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• Experimental Determination of L-R curves

Ligand-Response Relationships

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Ligand-Response Relationships

• Experimental Determination of L-R curves

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Ligand-Response Relationships

• Agonist 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

• 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

Ligand-Receptor Theories

• Clark’s occupancy theory

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E

Emax =[ DR ]

[RT]=

[D]

KD + [D]KD = EC50

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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

=Emax of a drug

Emax of the most active agonist in the same structural series

E

Emax =[ DR ]

[RT]=

[D]

KD + [D]

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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, itdepends 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

Drug Action and Design

• Agonists

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Drug Action and Design

• Agonists

24X activity

400X activity

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• Antagonists

Drug Action and Design

• Case study 1 – CNS drugscitalopram – antagonist antidepressant

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Drug Action and Design

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Drug Action and Design

• Case study 1 – CNS drugscitalopram – antagonist antidepressant

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Drug Action and Design

• Case study 1 – CNS drugscitalopram

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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

vasodilationdecreases blood glucose level

pupil constriction

causes impotence

decreases heart ratedecreases blood pressure

increase in gut secretionsand motility

bronchocontsrictiondecreases blood glucose

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Drug Action and Design

• Case study 2 – selective β blockers (β adrenoreceptor antagonists in the heart)