Pharmacology of Purinergic Receptors

Purinergic Receptors : 

Purinergic Receptors By : Vinayak D.Thorat. M.Pharm-I (Pharmacology) S.K.B College of Pharmacy, New Kamptee, Nagpur.

Introduction: : 

Nucleosides, especially adenosine, and nucleotides, especially ADP and ATP, produce a wide range of pharmacological effects. Cardiac slowing Fall in blood pressure Vasodilatation Inhibition of intestinal movements. Introduction: 2

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Purines are now known to participate in many physiological control mechanisms, such as the regulation of coronary flow, myocardial function, platelet aggregation, immune and neurotransmission, in both the CNS and PNS. The full complexity of purinergic control systems, and their importance in many pathophysiological mechanisms, is only now emerging, and therapeutic agents affecting these systems will assume growing significance. 3

Synthesis of ATP and Adenosine : 

Purines as mediators. ATP (and in platelets, ADP) is stored in vesicles and released by exocytosis. It is also present in the cytosol of all cells, from which large quantities may be released by cellular damage. Adenosine is present in the cytosol of all cells and is taken up and released via a specific membrane transporter. Released ATP and ADP are rapidly converted to adenosine by the action of tissue nucleotidases. Synthesis of ATP and Adenosine 4

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Classification : : 

Purine receptors P1 receptors P2 receptors (Adenosine receptor) (ATP receptors) (subtypes A1, A2 and A3) (subtypes P2X and P2Y ) Classification : 6

A1 receptor : : 

Location: Widely distributed throughout the body Superclass: GPCR Effector mechanism: Inhibition of cAMP Increase K+ permeability Agonist:N6-cyclopentyladenosine Antagonist:8-Cyclopentyltheophylline functions: Inhibitory action in brain. Regulate myocardial oxygen consumption and coronary blood flow. Decreases heart rate. A1 receptor : 7

A2A receptor: : 

Location: Striatum, nucleus accumbens, olfactory tubercle region of mammalian brain. Superclass: GPCR Effector mechanisms: Activation of adenyl cyclase. Inhibition of cAMP. Increase K+ permeability. Agonist: Isradefylline Antagonist CGS-21680 Functions: Vasodialation in coronary artery. Increases blood flow to myocardium. A2A receptor: 8

A2B receptor: : 

Location: Distributed throughout the CNS and peripherally. Superclass: GPCR Effector mechanism : Inhibition of adenyl cyclase. Agonist: NECA(N- ethyl carboxamidoadenosine) Antagonist: MRS-1706,MRS-1754. A2B receptor: 9

A3 receptor: : 

Location: Distributed in low level in brain. Superclass: GPCR Effector mechanism: Inhibition adenyl cyclase. Agonist: CIIB- MECA Antagonist:MRS1191, MRS 1523 Function: Inhibition of some specific signal pathway of adenosine. Inhibition of growth in human melanoma cells. A3 receptor: 10

P2 receptor : 

P2X P2Y Ligand gated G- protein coupled Ion channel receptors receptors Specific for ATP Low affinity for ATP P2 receptor 11

Groups according to ATP affinity: : 

Group 1: P2X1 and P2X3- high affinity to ATP. Group 2: P2X2, P2X4, P2X5 and P2X6- low affinity for ATP. Group 3 : P2X7 very low affinity to ATP. Groups according to ATP affinity: 12

P2X receptor: : 

Subunits themselves are not functional entities. Functional receptor channels are non selective Ca+, Na+, K+ and mediate rapid neurotransmission process is form by multimeric combination of various P2 receptor subunits. P2X receptor are LGIC receptor; unless not stated. P2X receptor: 13

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Functions are still unclear, P2x1-Expressed on various smooth muscle cells. ATP is a co-transmitter released by sympathetic nerves . P2x2-Expressed in many brain regions and mediate ‘fast transmission’ by ATP in the brain. P2x3-Occur in nociceptive afferent neurons and may participate in pain associated with ATP released through tissue injury. P2X7-Activation causes a large and non-selective increase in membrane permeability. Expressed mainly by cells of the immune system. Control the release of certain cytokines. 14

P2Y receptors: : 

All are member of GPCRs superfamily activated by both purine and pyrimidine nucleotides. Subtypes: Only five mammalian subtype are designated P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 , shows functional activity. Effector pathway: IP3 activation and subsequential release of calcium from intracellular stores. P2Y receptors: 15

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The other actions of ATP are mediated through P2Y-receptors, Of which five subtypes occur in mammals. They are GPCRs and are linked to various second messenger systems. They occur in many tissues, and the lack of selective antagonists makes it difficult to define their functions individually. Though the actions of ADP on platelets and vascular endothelial cells are ascribed to the P2y1-subtype. Drugs acting selectively on P2-receptors have not yet been developed for clinical purposes. 16

Therapeutic potential: : 

CVS: Antihypertensive: Adenylyl compounds : Negative inotropic and chronotropic effect on heart through A1 receptor. Adenosine regulates : Coronary blood flow, AV conduction , SA node excitation. Therapeutic potential: 17

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Anti psychotic effect: Adenosine agonist through A2 receptor inhibits amphetamine induced climbing activity and locomotor stimulation. Parkinson’s disease treatment: Selective A2A antagonist potentiates D2 mediated locomotor effects. A2 agonist potentiation of D2 antagonist mediated catalepsy. 18

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Anti arrhythmic effect: Adenosine is drug of choice for supra ventricular tachycardia. CNS: Migraine : Pre headache phase: Vasoconstriction, decreased coronary blood flow. Headache phase: Vasodialation, increase cerebral blood flow. 19

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Lungs and respiratory system: Adenosine : vasoconstriction of blood vessel in lungs. Asthma treatment : Adenosine causes concentration related bronchoconstriction. Enprofylline selective A2B antagonist is novel candidate in treatment of asthma. 20

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Thank you…….