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Dopamine

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types of receptors agonists and antagonists

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Dopamine

  1. 1. For the Subject MOLECULAR PHARMACOLOGY Submitted by- AMBADAS MANE Teacher In-Charge Mrs. SWATI KOLHE 1 An Assignment Submitted as a part of the Continuous Assessment-1 on the Topic DOPAMINE RECEPTORS All India Shri Shivaji Memorial Society’s College of Pharmacy, Kennedy Road, Pune-411001
  2. 2. CONTENT 2  Introduction  Structure Of Dopamine Receptor  Roles Of Dopamine  Synthesis  Degradation  Types Location And Distribution  Dopaminergic Pathways  Receptor Agonist Antagonist And Therapeutic Use  Parkinson  Schizophrenia  Recent Researches
  3. 3. DOPAMINE 3  Dopamine (contracted from 3,4-dihydroxyphenethylamine)  Particularly important in relation to neuropharmacology as involved in several common disorders of brain function like 1.Parkinson’s disease 2.Schizophrenia and 3.Attention deficit disorder  The distribution of dopamine in the brain is more restricted than that of noradrenaline.  High concentration in 1.corpus striatum 2.frontal cortex 3.limbic system 4.hypothalamus
  4. 4. STRUCTURE OF DOPAMINE RECEPTOR 4
  5. 5. Roles of Dopamine 5 • Role in movement • Role in pleasure and motivation • Controls the flow of information from other areas of the brain
  6. 6. Synthesis 6 L-phenylalanine (amino acid from diet) phenylalanine hydroxylase L- Tyrosine Tyrosine hydroxylase L- Dopa Dopa decarboxylase Dopamine (DA) Monoamine oxidase (MAO) Catechol-O-methyl transferase (COMT) DOPAC + HVA
  7. 7. The primary and minor metabolic pathways: 7  Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine  Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine  Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → Dopamine
  8. 8. DEGRADATION 8  Dopamine is broken down into inactive metabolites by a set of enzymes 1. Monoamine oxidase (MAO), 2. Catechol-O-methyl transferase (COMT), and 3. Aldehyde dehydrogenase (ALDH), acting in sequence.  Different breakdown pathways exist but the main end-product is homovanillic acid (HVA) that has no known biological activity.
  9. 9. Dopamine Receptors 9 •There are five types of dopamine receptors. D1,D2,D3,D4,D5. •We can categorize dopamine receptors in two two main subtypes: 1.D1 like receptor family: the Gs protein is involved and adenylyl cyclase would be activated. The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP). 2.D2 like receptor family: which is the receptor combining with the Gi protein and its activated alphasubunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced.
  10. 10. LOCATION AND DISTRIBUTION 10
  11. 11. 11
  12. 12. Dopaminergic Pathways 12  Mesolimbic Pathway  Mesocortical Pathway  Nigrostriatal Pathway  Tuberoinfundibular Pathway  Incertohypothalamic Pathway  Medullary Periventricular  Retinal
  13. 13. Significance of Dopaminergic Pathways 13  Mesolimbic Pathway – Associated with pleasure, reward and goal directed behaviour  Mesocortical Pathway – Associated with motivational and emotional responses  Nigrostriatal Pathway – Involved in coordination of movement (part of basal ganglia motor loop/EPS)  Tuberoinfundibular Pathway – Regulates secretion of prolactin by pituitary gland and involved in maternal behavior
  14. 14. D1 receptors 14  Most abundant receptor in the central nervous system  Lack of introns  446 Amino acids  Highly expressed in basal ganglia  chromosome 5
  15. 15. D5 15 •Intron less •477 Amino acids •50% homology with D1 •Chromosome 4 •Expression in nucleus of thalamus; suggesting that role in pain stimuli
  16. 16. D2 16 •7 introns •Third cytoplasmic domain is long and the carboxyl terminus is short •Chromosome 11 •Activation of potassium channel , potentiation of arachidonic acid release
  17. 17. D3 17 •Five introns •446 Amino acid •Chromosome 3 •As a functional receptor remains uncertain •Recent study shows it might mediate positive regulatory influences of Da on production of neurotension.
  18. 18. D4 18 •4 introns •387 Amino acids •Homology with D2 and D3 41% and 39% •Chromosome 11 •Hippocampous and frontal cerebral cortex
  19. 19. TYPES and FUNCTION 19
  20. 20. RELEASE OF DOPAMINE 20
  21. 21. Dopamine 1 (DA1) Receptor agonists 21 •Fenoldopam •Piribedil •Ibopamine •SKF 3893 •Apomorphine
  22. 22. Therapeutic uses of DA1 Receptor Agonists 22 •Decreases peripheral resistance •Inducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone •Increases in activity of the renin aldosterone system
  23. 23. Dopamine 2 (DA 2) Receptor Agonists 23 •Bromocriptine •Pergolid •Lisuride •Guinpirole •Carmoxirole
  24. 24. Theraputic uses of DA2 receptor agonists 24 •Used for treating Parkinson’s disease •Inhibits prolactin release (which decreases tumor size)
  25. 25. DA 1 Receptor Antagonists 25 •SCH23390 •Clozapine Therapeutic uses Used for treating schizophrenia
  26. 26. DA 2 Receptor Antagonists 26 •Metoclopramid •Domperidone •Sulpiride •Haloperidol Therapeutic uses •Gastric Motility Disorders
  27. 27. Parkinson’s Disease 27  Substantial loss of Dopamine in the striatum (70 – 80%)  Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic systems)  Treatment strategy includes increasing dopamine levels by administering L-Dopa, nerve grafting with dopamine containing cells and deep brain stimulation
  28. 28. Schizophrenia 28  Defective dopamine neurotransmission – relative excess of central dopaminergic activity  An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems  Behavior similar to the behavioral effects of psychostimulants  Antipsychotics such as chlorpromazine, bind to D2 dopamine receptors and reduced positive psychotic symptoms
  29. 29. Recent researches 29  Anti-insulin  Analgesic  Role in apoptosis  Memory  Immune
  30. 30. Summary 30 • Neurotransmitter that acts as a modulator • 2 family of receptors for dopamine • 3 main pathways of action
  31. 31. REFERENCES 31  Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th edi; chap 15,16,22: 932-964  Bertram Katzung ; Basic and clinical pharmacology ; Drug of abuse ;553- 568 ;12th edition 2012.  Rang H.P. and Dale M.M;Antipsychotics;7th edition; 39,45,49; 557  www.Wikipedia.com
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