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Adenosine Receptors
03-03-2017 1
Presented by Kamlesh V. Warokar
M.Pharm ( Dept. of Pharmacology)
Sinhgad Institute of Pharmacy, Pune.
• Introduction
• Adenosine Receptors
• Drugs
• Therapeutic Role of AR
• Drugs in Clinical Trial
• Key References
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CONTENT
AdenosineIntroduction:• Adenosine is naturally occurring endogenous purine
nucleoside.
• Adenosine is made up of adenine
attached to a ribose.
• Chemical formula: C10H13N5O4
• Plasma level: 0.04 – 0.2 µmol.
• t ½ : 10 sec.
.
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• Metabolite of ATP.
• It is released by nearly all cells and is generated in the
extracellular space.
• Adenosine is extracellularly signalling agent within the
CNS and PNS.
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• It act as a neuromodulator
• Cellular energy transfer
• Ischemic preconditioning
Functions of adenosine
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Adenosine Receptor
(AR)
AR• Purinergic G-protein coupled receptor.
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Purinergic receptors
P1 (Adenosine)
A1
A2A2A
A2BA3
P2P2X
P2Y
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• There are four types of AR.
• Each receptors are encoded by a separate gene and has
different function.
• ARs are widely distributed throughout the body basically
all cells.
Structure of AR
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• It is Hepthahelical G-Protein
coupled receptors.
• Having different amino acids as
- A1-AR (326),
- A2A-AR (412),
- A2B-AR (328) and
- A3-AR (318).
• A1 receptor is most conserved AR sub-type among
species.
• It is widely expressed throughout the body.
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A1-AR
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Brain, Eye,
Adrenal Gland, Atria
Skeletal Muscle, Liver, Kidney,
Adipose Tissue, Salivary Glands,
Esophagus, Colon, Testis,
Antrum
Lung (Bronchi), Pancreas
Distribution
• cAMP
• A1 receptors modulate neuronal activity by blocking
neurotransmitter release and reducing the firing
rate.
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K+
Mechanism
A1
Gi
Go
Effects of receptorsCNS:• Decrease neurotransmitter release• Sedation
CVS:• -ve chronotropy• -ve inotropy• -ve dromotropy• Inhibit L-type Ca+ channels
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RENAL:• Inhibits renin release• Vasoconstriction of afferent arteriole
METABOLIC:• Inhibits lipolysis
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• It act as a neuromodulators.
• It is sub-divided into two receptors as
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A2-AR
A2B-AR
A2A-AR
A2-AR
• Having high agonist affinity.
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A2A-AR
Spleen, Thymus,
Leukocyte, Blood
Platelets, Tuberculum,
Olfactory Bulb
Heart, Lung, Blood
Vessels
Other brain
regions
Mechanism
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Golf
olf
A2A-AR
GS
cAMP
• olf – olfactory receptor
Effects of receptors
CNS:• Modulate neurotransmission of GABA, Glutamate
CVS: • Coronary and peripheral vasodilation
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• Low agonist affinity.
• It is most insensitive adenosine receptor among all
four ARs, requiring micromolar adenosine conc.
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A2b-AR
Cecum, Colon,
Bladder
Lung, Blood
Vessels, Eye, Mast
Cells
A.T, Brain,
Kidney, Liver, Ovary
Mechanism
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q/11Gq
A2B-AR
GS
cAMP
• q – heteromeric receptor
PULMONARY:• Vasodilation• Mast cell release of IL-8
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Effects of receptors
• It is less widely distributed in body.
• A3 receptor is binds with Gi and Go which inhibits
adenylyl cyclase activity.
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A3-AR
Testis (Rat), Mast Cell (Rat)
Cerebellum,
Hippocampus
Thyroid,
Brain Adrenal Gland, Liver
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Go
A3-AR
Gi
cAMP
Mechanism
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Adenosine receptors
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Drugs classification
Agonist
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Adenosine
• Marked hyperpolarization and suppression of calcium
dependent actions potential.
• Inhibits AV nodal conduction and increases period.
• Use: Paroxysmal Supraventricular Tachycardia.
• t ½ : 10 sec.
• ADR: flushing, rashes, metallic taste
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adenosine
Other agonist • Methotrexate
• Dipyridamole
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Antagonist
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Mechanism
• Caffeine.mp4• https://www.youtube.com/watch?
v=YuJOhpNS0IY
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caffeine• Nonspecific adenosine receptors antagonist.
• Competitive nonselective phosphodiesterase inhibitors.
• Use:
- CNS stimulant,
- Cardiac muscle stimulant,
- Bronchoconstriction.
• Aminophylline
• Istradefylline
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Other antagonist
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Therapeutic role
CNso Anaesthesia and intensive care:
• Adenosine blocks nociceptive transmission
• IV adenosine infusion-analgesia at 50-70 mg/kg/min.
• Reduces ischaemic pain.
• e.g.: Remifentanil.
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o Epilepsy
• Astrogliosis – hallmark of epileptogenesis.
• Adenosine – inhibitory modulator of brain activity.
• Activation of A1 receptor.
• Adenosine kinase – major metabolic enzyme.
• e.g.: GP 515 tested – reduced kindlled seizures in rats.
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CNs
o Parkinsons disease:
• A2A receptors antagonist
• e.g.: Istradefylline
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CNs
o Dementia and anxiety disorders
• FR 194921
o Pain
• GW 493838
o Sleep
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CNs
o Ischaemia:
• Ischaemic preconditioning
- Adenosine theory.
• Adenosine reduces ischaemia by
- Improved tissue perfusion.
- Anti-inflammatory action.
- Direct intracellular effect .
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Cvs
o Arrhythmia:
• Effects by activation of A1-AR.
• Reduction in HR and atrial contractility.
• e.g.: Adenocard.
o Vasodilation:
• A2-AR involved in vasodilation.
• e.g.: Adenoscan.
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Cvs
o Bronchial Asthma:
• Stable form of adenosine – AMP.
• Adenosine levels increase in BAL fluid and cause
hyperesponsiveness in airways.
• Adenosine receptors antagonist.
• e.g.: Theophylline.
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Respiratory system
o IBD:
• Role of adenosine in inflammation.
• A2A and A3 receptors.
• Reduces leucocyte infiltration and proinflammatory
cytokines.
• e.g.: IB-MECA – A3 agonist tested in DNBS induced
colitis in mice.
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GIT
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CANCER• A3 AR agonist can attenuate
apoptosis.
• e.g.: CI-IB-MECA
• High concentration more than
10 µM.
VISUAL DISORDERS• A3-AR in knockout mice had significantly lower
intraocular pressure.
• A3-AR antagonist have potential in treatment of
glaucoma.
• Suitable for human only.
• e.g.: OT-7999
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Drugs in clinical trial
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GW493838
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CAPADENOSON
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PRELADENANT
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ROLOFYLLINE
Key references
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1. Gary L. Stilest, “Adenosine Receptors”, The Journal of Biological
Chemistry, (1996) 6451-6454.
2. Bertil B. Fredholm, Adriaan P. Ijzerman, Kenneth A. Jacobson, Karl N.
Klotz, Joel Linden, “Nomenclature and Classification of Adenosine
Receptors”, The American Society for Pharmacology and Experimental
Therapeutics, (2001) 527-553.
3. Jiang F. Chen, Holger K. Eltzschig, Bertil B. Fredholm, “Adenosine
Receptors as Drug Targets”, NIH Public Access National Review of Drug
Discovery, (2013) 265-286.
4. Catarina V. Gomes, Manuella P. Kaster, Angelo R. Tome, Paula M.
Agostinho, Rodrigo A. Cunha, “Adenosine Receptors and Brain Diseases”,
Biochimica et Biophysica Acta, (2011) 1380-1399.
5. Joel Linden, “Structure and Function of A1 Adenosine Receptor”, The Journal
of Federation of American Societies for Experimental Biology, (2000) 2668-
2676.
6. Per Svenningsson, Bertil B. Fredholm, Rodrigo A. Cunha, “Pharmacology of
Adenosine A2A Receptor and Therapeutic Application”, Current Affairs in
Medicinal Chemistry, (2008) 1349-1364.
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7. Stefania Gessi, Stefania Merighi, Kalia Varani, Pier Borea, “The A3
Adenosine Receptors: An Enigmatic Player in Cell Biology”,
Pharmacology and Therapeutics, (2008) 123-140.
8. Kenneth A. Jacobson, Zhan G. Gao, “Adenosine Receptors as Therapeutic
Targets”, National Review of Drug Discovery, (2008) 247-264.
9. Sakshi Sachdeva, Monika Gupta, “Adenosine and its Receptors as
Therapeutic Targets: An Overview”, (2012) 246-250.
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