Dopamine

Dopamine

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  1 DOPAMINE RECEPTOR MOLECULAR PHARMACOLOGY PRESENTEDBY –MANOJ KASHYAP ROLL 18162030 DEPARTMENT OF PHARMACEUTICAL ENGINEERING AND TECHNOLOGY, IIT BHU VARANASI
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  CONTENT 2  Introduction  StructureOf Dopamine Receptor  Roles Of Dopamine  Synthesis  Degradation  Types Location And Distribution  Dopaminergic Pathways  ReceptorAgonistAntagonistAnd Therapeutic Use  Parkinson  Schizophrenia  Recent Researches
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  DOPAMINE 3  Dopamine (contractedfrom 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
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  STRUCTURE OF DOPAMINERECEPTOR 4
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  Roles of Dopamine •Role in movement 5 • Role in pleasure and motivation • Controls the flow of information from other areas of the brain
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  Synthesis L-phenylalanine (amino acidfrom diet) phenylalanine hydroxylase L- Tyrosine Tyrosine hydroxylase L- Dopa Dopa decarboxylase Dopamine (DA) Monoamine oxidase (MAO) Catechol-O-methyl transferase (COMT) DOPAC + HVA6
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  The primary andminor metabolic pathways:  Primary: L-Phenylalanine → L-Tyrosine → L-DOPA→ Dopamine  Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine 7
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  DEGRADATION  Dopamine isbroken 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. 8  Different breakdown pathways exist but the main end-product is homovanillic acid (HVA) that has no known biological activity.
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  Dopamine Receptors •There arefive 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
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  LOCATION AND DISTRIBUTION 10
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  Dopaminergic Pathways  MesolimbicPathway  Mesocortical Pathway  Nigrostriatal Pathway  Tuberoinfundibular Pathway  Incertohypothalamic Pathway  Medullary Periventricular  Retinal 12
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  Significance of DopaminergicPathways  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 13
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  D1 receptors  Mostabundant receptor in the central nervous system  Lack of introns  446 Amino acids  Highly expressed in basal ganglia  chromosome 5 14
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  D5 •Intron less •477 Aminoacids •50% homology with D1 •Chromosome 4 •Expression in nucleus of thalamus; suggesting that role in pain stimuli 15
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  D2 •7 introns •Third cytoplasmicdomain is long and the carboxyl terminus is short •Chromosome 11 •Activation of potassium channel , potentiation of arachidonic acid release 16
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  D3 •Five introns •446 Aminoacid •Chromosome 3 •As a functional receptor remains uncertain •Recent study shows it might mediate positive regulatory influences of Da on production of neurotension. 17
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  D4 •4 introns •387 Aminoacids •Homology with D2 and D3 41% and 39% •Chromosome 11 •Hippocampous and frontal cerebral cortex 18
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  RELEASE OF DOPAMINE 19
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  Dopamine 1 (DA1)Receptor agonists •Fenoldopam •Piribedil •Ibopamine •SKF 3893 •Apomorphine 20
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  Therapeutic uses ofDA1 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 21
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  Dopamine 2 (DA2) ReceptorAgonists •Bromocriptine •Pergolid •Lisuride •Guinpirole •Carmoxirole 22
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  Theraputic uses ofDA2 receptor agonists •Used for treating Parkinson’s disease •Inhibits prolactin release (which decreases tumor size) 23
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  DA 1 ReceptorAntagonists •SCH23390 •Clozapine 24 Therapeuticuses Used for treating schizophrenia
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  DA 2 ReceptorAntagonists •Metoclopramid •Domperidone •Sulpiride •Haloperidol Therapeuticuses •Gastric Motility Disorders 25
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  Parkinson’s Disease  Substantialloss 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 26
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  Schizophrenia  Defective dopamineneurotransmission – 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 27
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  Recent researches  Anti-insulin Analgesic  Role in apoptosis  Memory  Immune 28
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  REFERENCES  Goodman andGilman’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 29
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