Adenosine

Receptors
Presented by
Kamlesh V. Warokar
M.Pharm
( Dept. of Pharmacology)

Sinhgad Institute of Pharmacy, Pune.

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 • Introduction

• Adenosine Receptors

• Drugs

• Therapeutic Role of AR

• Drugs in Clinical Trial

• Key References

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 Introduction:
• 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

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 Adenosine Receptor
(AR)

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 • Purinergic G-protein coupled receptor.

A1
A2A
P1 (Adenosine) A2
A2B
Purinergic A3
receptors
P2X
P2
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.

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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).

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 • A1 receptor is most conserved AR sub-type among
species.

• It is widely expressed throughout the body.

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 Brain,
Eye, Skeletal Muscle, Liver, Kidney,
Adrenal
Gland, Adipose Tissue, Salivary Glands,
Atria
Esophagus, Colon, Testis, Lung
(Bronchi),
Antrum Pancreas

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 Gi
• A1
cAMP K+

Go

• A1 receptors modulate neuronal activity by blocking

neurotransmitter release and reducing the firing
rate.

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 CNS:
• 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

A2-AR

A2A-AR A2B-AR

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 • Having high agonist affinity.

Spleen,
Thymus,
Leukocyte,
Blood Other
Heart, Lung, Blood brain
Platelets,
Tuberculum, Vessels regions
Olfactory
Bulb

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 GS
olf
A2A-AR cAMP

Golf

• olf – olfactory receptor

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 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.

Cecum, A.T,
Colon, Lung, Blood Vessels, Brain,
Bladder Kidney,
Eye, Mast Cells
Liver,
Ovary

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 GS
A2B-AR cAMP
q/11
Gq

• q – heteromeric receptor

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 PULMONARY:
• Vasodilation
• Mast cell release of IL-8

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 • It is less widely distributed in body.

• A3 receptor is binds with Gi and Go which inhibits

adenylyl cyclase activity.

Testis
(Rat),
Mast Cerebellum, Thyroid,
Cell Brain
(Rat) Hippocampus Adrenal
Gland,
Liver

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 Gi
A3-AR cAMP
Go

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 Drugs
classification

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 Adenosine

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 • 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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 • Methotrexate

• Dipyridamole

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 • Caffeine.mp4
• https://www.youtube.com/watch?v=YuJOh
pNS0IY

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 • Nonspecific adenosine receptors antagonist.
• Competitive nonselective phosphodiesterase inhibitors.
• Use:
- CNS stimulant,
- Cardiac muscle stimulant,
- Bronchoconstriction.

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 • Aminophylline

• Istradefylline

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 o 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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 o Parkinsons disease:

• A2A receptors antagonist

• e.g.: Istradefylline

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 o Dementia and anxiety disorders

• FR 194921

o Pain

• GW 493838

o Sleep

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 o Ischaemia:

• Ischaemic preconditioning

- Adenosine theory.

• Adenosine reduces ischaemia by

- Improved tissue perfusion.

- Anti-inflammatory action.

- Direct intracellular effect .

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 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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 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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 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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 • A3 AR agonist can attenuate
apoptosis.

• e.g.: CI-IB-MECA

• High concentration more than

10 µM.

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 • 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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 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.

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 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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