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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