new target for the parkinson disease

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DOPAMINE RECEPTOR
MOLECULAR PHARMACOLOGY
PRESENTED BY –MANOJ KASHYAP
ROLL 18162030
DEPARTMENT OF PHARMACEUTICAL ENGINEERING AND TECHNOLOGY, IIT BHU VARANASI

2. CONTENT
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 Introduction
 Structure Of Dopamine Receptor
 Roles Of Dopamine
 Synthesis
 Degradation
 Types Location And Distribution
 Dopaminergic Pathways
 ReceptorAgonistAntagonistAnd Therapeutic Use
 Parkinson
 Schizophrenia
 Recent Researches

3. DOPAMINE
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 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. STRUCTURE OF DOPAMINE RECEPTOR
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5. Roles of Dopamine
• Role in movement
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• Role in pleasure and motivation
• Controls the flow of information from other areas of the brain

6. Synthesis
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 + HVA6

7. The primary and minor metabolic pathways:
 Primary: L-Phenylalanine → L-Tyrosine → L-DOPA→ Dopamine
 Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine
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8. DEGRADATION
 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.
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 Different breakdown pathways exist but the main end-product is homovanillic
acid (HVA) that has no known biological activity.

9. Dopamine Receptors
•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.9

10. LOCATION AND DISTRIBUTION
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12. Dopaminergic Pathways
 Mesolimbic Pathway
 Mesocortical Pathway
 Nigrostriatal Pathway
 Tuberoinfundibular Pathway
 Incertohypothalamic Pathway
 Medullary Periventricular
 Retinal
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13. Significance of Dopaminergic Pathways
 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
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14. D1 receptors
 Most abundant receptor in the central nervous system
 Lack of introns
 446 Amino acids
 Highly expressed in basal ganglia
 chromosome 5
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15. D5
•Intron less
•477 Amino acids
•50% homology with D1
•Chromosome 4
•Expression in nucleus of thalamus; suggesting that role in pain stimuli
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16. D2
•7 introns
•Third cytoplasmic domain is long and the carboxyl terminus is short
•Chromosome 11
•Activation of potassium channel , potentiation of arachidonic acid
release
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17. D3
•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.
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18. D4
•4 introns
•387 Amino acids
•Homology with D2 and D3 41% and 39%
•Chromosome 11
•Hippocampous and frontal cerebral cortex
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19. RELEASE OF DOPAMINE
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20. Dopamine 1 (DA1) Receptor agonists
•Fenoldopam
•Piribedil
•Ibopamine
•SKF 3893
•Apomorphine
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21. Therapeutic uses of DA1 Receptor Agonists
•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
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22. Dopamine 2 (DA 2) ReceptorAgonists
•Bromocriptine
•Pergolid
•Lisuride
•Guinpirole
•Carmoxirole
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23. Theraputic uses of DA2 receptor agonists
•Used for treating Parkinson’s disease
•Inhibits prolactin release (which decreases tumor size)
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24. DA 1 ReceptorAntagonists
•SCH23390
•Clozapine
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Therapeutic uses
Used for treating schizophrenia

25. DA 2 ReceptorAntagonists
•Metoclopramid
•Domperidone
•Sulpiride
•Haloperidol
Therapeutic uses
•Gastric Motility Disorders
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26. Parkinson’s Disease
 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
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27. Schizophrenia
 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 DAsystems
 Behavior similar to the behavioral effects of psychostimulants
 Antipsychotics such as chlorpromazine, bind to D2 dopamine receptors
and reduced positive psychotic symptoms
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28. Recent researches
 Anti-insulin
 Analgesic
 Role in apoptosis
 Memory
 Immune
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29. REFERENCES
 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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