medicinal chemistry/ chem 458/658 chapter 8-...
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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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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)