3. Purinergic receptors
Present in most organ systems
Extracellular purines (Adenosine, ADP, ATP)
Extracellular pyrimidines (Uridine, UDP, UTP)
Mediate biological effects via P rs
Classification :
5. Adenosine
Metabolite of ATP
Naturally occurring endogenous purine nucleoside
Adenosine is made up of adenine attached to a ribose.
Chemical name: 6-amino-9-beta-D-ribofuranosyl-9-H-purine.
Plasma adenosine level : 0.04 - 0.2 µmol.
Short t 1/2 : 10s
Functions of adenosine:
Neuromodulator, cellular energy transfer, signal of inflammation,
ischaemic preconditioning.
6. Adenosine-
Neurotransmitter??
It is neither stored in synaptic vesicles nor it acts exclusively on
synapses
Release & uptake: mediated by bidirectional nucleoside transporter
Neuromodulator:
Presynaptic: controls NT release
Postsynaptic: hyper/depolarizes the neurons
Non synaptic: regulates the effect on glial cells
Characteristics of NT:
Adenosine producing enzymes present in synapse
Actions via interaction with Rs
Actions can be blocked by specific antagonist
Actions can be terminated by reuptake and metabolic syndrome
11. Effects of the receptors
RENAL:
Inhibits renin release
Increase Na reabsorption in PCT
Vasoconstriction of afferent arteriole-reduces GFR
Metabolic:
Inhibits lipolysis
Increases insulin sensitivity
13. Effects of the receptors
CVS:
Coronary and peripheral vasodilation
Inhibits platelet aggregation
CNS:
Modulate the neurotransmission of GABA,
Ach, glutamate → Motor activity
19. Effects of the receptors
Pulmonary:
Mast cell release of allergic mediators
20. Distribution and expression of P1 receptors
Expression
level
A1 receptors A2A
receptors
A2B receptors A3 receptors
High
expression
Brain (cortex,
hippocampus,
cerebellum),
spinal cord, eye,
adrenal gland,
atria
Blood
platelets,
olfactory bulb
Spleen,
thymus,
leukocytes
Cecum, colon,
bladder
Testis (rat),
mast cells (rat)
Intermediat
e
expression
Other brain
regions, skeletal
muscles, liver,
kidney, adipose
tissue
Heart, lung,
blood vessels,
peripheral
nerves
Lung, blood
vessels, eye,
mast cells
Cerebellum,
hippocampus
Low
expression
Lungs (but
probably higher in
bronchi),
pancreas
Other brain
regions
Adipose tissue,
adrenal gland,
brain, kidney
Thyroid, most
of brain
adrenal gland,
spleen, liver,
21. Adenosine receptors
RECEP
TOR
GENE MECHANISM AGONIST ANTAGONIST
A 1 ADORA 1 G i - ↓cAMP N 6
Cyclopentoaden
osine
Caffeine,
theophylline
A 2 a ADORA 2 a G s - ↑cAMP Regadenoson Caffeine,
theophylline,
istradefylline
A 2 b ADORA 2 b G s - ↑cAMP 5 N
Ethylcarboxamid
oadenosine
Theophylline,
CVT-6883, MRS-
1706
A 3 ADORA 3 G i - ↓cAMP N methyl
adenosine,
IB-MECA
Theophylline,
MRS-1191,
1220,1334
23. Respiratory system
Bronchial asthma:
Stable form of adenosine – AMP - broncho
constriction
Adenosine levels increased in BAL fluid and cause
hyperresponsiveness in airways
Adenosine receptor antagonist-theophylline &
selective A1 receptor antagonist- bamiphylline
24. Respiratory system
Refractory primary pulmonary hypertension:
Routine treatment
Adenosine infusion for refractory cases
Mechanism-Pulmonary vasodilation by A2
receptors
Increase AMP-vascular smooth muscle relaxation
Stimulation of K+ ATPase channel
25. CNS
Anaesthesia and intensive care:
Adenosine blocks nociceptive transmission
IV adenosine infusion-analgesia at 50-70 mg/kg/min
Reduces ischaemic pain
Adenosine infusion during GA- good recovery and
sustained post op pain relief
Superior to remifentanil
26. CNS
Epilepsy:
Astrogliosis - hallmark of epileptogenesis
Adenosine-inhibitory modulator of brain activity
Activation of A1 receptors
Adenosine kinase- major metabolic enzyme
predominantly expressed in adult brain
ADK inhibitor GP 515 tested-reduced kindled seizures in
rats
31. GIT
Inflammatory bowel disease:
Role of adenosine in inflammation
A2a and A3 receptors
Reduces leucocyte infiltration and proinflammatory
cytokines
IB-MECA - A3 agonist tested in DNBS induced colitis in
mice
32. Bacterial Sepsis:
Acadesine, adenosine precursor injected iv in
mongrel pigs following soft tissue injury and shock
72 hrs later E.coli 0111:B4 endotoxin given, effects
observed were:
Reduction in endotoxin induced hypoxia and
pulmonary hypertension
Reduction in fluid requirement
Reduction in mortality and prolonged survival time
33. Immunity
Adenosine accumulation and stimulation of (?A2)
receptors has been implicated in the
immunosuppression seen in critical illness
A3 receptor stimulation may inhibit tumour growth,
perhaps melanomas, colon or prostate carcinoma,
and lymphomas. Peripheral blood monocytes
produce G-CSF when stimulated by adenosine
34. Disease susceptibility
Single nucleotide polymorphisms in the A1: Aspirin intolerant
asthma
Alterations in ADORA1 gene: Change in infarct size in patients
with ischaemic infarct size
SNPs in ADORA2A gene: Anxiety disoroders
SNPs in ADORA2A gene: Stopping Mtx Rx for RhA due to
ADR(GIT) but not efficacy
High expression of A2A Rs : Pts with unexplained syncope
Up regulation of A2A Rs in endothelial cells: Lung cancer
Dysfunctional A2B Rs : impotence
36. Acupuncture
Mechanical deformation of the skin by acupuncture needles
appears to result in the release of adenosine.
A 2014 Nature Reviews Cancer review journal found that the
key mouse studies that suggested acupuncture relieves pain
via the local release of adenosine, which then triggered
close-by A1 receptors .
The anti-nociceptive effect of acupuncture may be mediated
by the adenosine A1 receptor.
37. Methotrexate
Methotrexate, which has strong anti-inflammatory properties,
inhibits the action of dihydrofolate reductase, leading to an
accumulation of adenosine.
Adenosine-receptor antagonist caffeine reverses the anti-
inflammatory effects of methotrexate.
38. Adenosine
Marked hyperpolarization and suppression of calcium-
dependent action potentials
inhibits AV nodal conduction and increases the AV nodal
refractory period
Use: paroxysmal supraventricular tachycardia
Half life: 10 seconds
ADR: Metallic taste, flushing, rashes, apprehension
39. Dipyridamole
Dipyridamole inhibits the phosphodiesterase
Adenosine reuptake inhibitor
Uses:
adjunct to coumarin anticoagulants in the prevention of
postoperative thromboembolic complications of cardiac valve
replacement
Pulmonary hypertension
Overdose: Rx – Xanthine derivatives
40. Caffeine
Nonspecific adenosine Rs antagonist
competitive nonselective phosphodiesterase inhibitor
Bronchodilator, CNS stimulant, cardiac muscle stimulant and
a diuretic.
Ischemic preconditioning
Caffeine for apnoea of prematurity
47. Selective A2a antagonists
Parkinson’s disease, drug addiction
Stimulate D2 receptors
Istradefylline: Phase III
Vipadenant: Parkinson’s : Monotherapy, adjunct:
{reclinical toxicological studies issues: Phase I
Preladenant: phase II
48. Selective A2B antagonists
Reversal insulin resistance in Type II DM
Inhibition of degranulation of human mast cells,
release of cytokines
Under development
49. Adenosine modulators
Allosteric modulators for adenosine receptors may have potential
therapeutic advantage.
A1
Allosteric enhancers - Antiarrhythmic and antilipolytic activity.
A2
Not yet been developed
Amiloride and analogues were demonstrated to be allosteric
inhibitors at A2A receptor
A3
Allosteric enhancers are -useful against ischemic conditions or as
antitumor agents.
Levels rise rapidly in ischaemic tissue due to adenosine kinase inhibition, and mediate ischaemic pre-conditioning, where a prior, brief episode of organ ischaemia protects against subsequent ischaemia!Inflamed tissues also release adenine nucleotides which are converted to adenosine. Cells that release these nucleotides include platelets, mast cells, nerves and the endothelium. Ecto-nucleotidases (CD39, CD73) then turn the nucleotides into adenosine.
S-Adnenosine homocystine
Bamiphylline - xanthines
Remifentanil – opioid analgesic used as adjunct in GA
DNBS- DiNitroBenzeneSulfoicAcid
It inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine.