Medicinal chemistry-I, Unit 2. Drug Acting On Sympathetic nervous system.pdf

Medicinal chemistry-I, Unit 2. Drug Acting On Sympathetic nervous system.pdf

• 1.
  Drug Acting onAutonomic Nervous system A. Sympathomimetic (Adrenergic agonist) B. Sympatholytic( Adrenergic antagonist) Alpha Blockers Beta Blockers Mr. Mote G.D. Asst. Prof, ADCBP, Ashta
• 3.
  NH2 HO HO Dopamine NH2 HO HO Nor epinephrine OH NH HO HO Epinephrine OH CH3
• 6.
  NH HO HO Epinephrine OH CH3 NH2 Phenyl alanine NH2 HO Tyrosine NH2 HO HO L-DOPA COOH COOH 1 2 NH2 HO HO Dopamine H NH2 HO HO NorEpinephrine OH 3 4 5 PAH TH LDOPA-DC DH NE-MT PAH-Phenyl alanine Hydroxylase TH-Tyrosine Hydroxylase LDOPA-DC- L-DOPA Decarboxylase DH-Dopamine hydroxylase NE-MT-Nor epinephrine Methyl transferase COOH Biosynthesis of Catecholamine's
• 7.
  Biosynthesis of Catecholamine's L- Dopamineenters in vesicles and hydrolysed into nor adrenaline by dopamine hydroxylase DOPA decarboxylated into Dopamine by DOPA Decarboxylase in cytoplasm of neuron L-Tyrosine hydrolysed into DOPA by tyrosine hydroxylase in cytoplasm of neuron Nor Adrenaline gets converted into adrenaline with the help of enzyme s- adenosine methionine and n-methyl transferase and after deploarisation it released into synapse
• 9.
  Catabolism of Catecholamine's CH OH NH2 HO HO MAO CH OH C HO HO O H CH OH NH HO HO CH3 Epinephrine Nor-Epinephrine(DOPGAL)3,4 dihydroxy phenyl glycoaldehyde) MAO COMT(Catecholamine O-methyl transferase CH OH NH2 H3CO HO CH OH NH H3CO HO CH3 Metanephrine Nor-Metanephrine MAO MAO CH OH C H3CO HO O H MOPGAL(3-Methoxy 4-hydroxy phenyl glycoaldehyde) CH OH C H3CO HO O OH AD(Aldehyde Dehydrogenase) VMA (vanillyl mandelic acid) CH OH C HO HO O OH DOMA(Dihydroxy Mandeliic acid) AD(Aldehyde Dehydrogenase) AR(Aldehyde Reductase) CH OH C H HO HO OH H DOPEG(3,4 dihydroxy phenyl glycol) CH OH C H H3CO HO OH H MOPEG(3methoxy -4-hydroxy polyethylene glycol) COMT ADH Alcohol dehydrogenase COMT
• 10.
  Catabolism of Catecholamine's Onestage • Epinephrine and Nor epinephrine methylated at hydroxyl group by Catecholamine O-Methyl transferase(COMT) into Metanephrine and non-Metanephrine respectively. • Metanephrine and non-Metanephrine are converted into MOPGAL(3 Methoxy 4-hydroxy phenyl glycoaldehyde ) by Mono amine oxidase(MAO) • MOPGAL(3 Methoxy 4-hydroxy phenyl glycoaldehyde ) is converted into Vanillyl mandelic acid(VMA)
• 11.
  Catabolism of Catecholamine's SecondStage • Epinephrine and Nor epinephrine oxidized by Mono amine oxidase(MAO) enzyme into DOGAL(3,4 Hydroxy phenyl glycoaldehyde) • into DOGAL(3,4 Hydroxy phenyl glycoaldehyde) is converted into DOPEG(3,4 dihydroxy phenyl glycol) by aldehyde reductase enzyme • DOPEG(3,4 dihydroxy phenyl glycol) is metabolized into MOPEG(3Methoxy 4 hydroxy polyethylene glycol) by enzyme COMT • MOPEG(3Methoxy 4 hydroxy polyethylene glycol) metabolized into MOPGAL(3-Methoxy 4-hydroxy phenyl glycoaldehyde) by enzyme alcohol dehydrogenase • MOPGAL(3-Methoxy 4-hydroxy phenyl glycoaldehyde) is metabolized into VMA(Vanillyl mandelic acid by aldehyde dehydrogenase enzyme
• 12.
  Catabolism of Catecholamine's Thirdstage • Epinephrine and Nor epinephrine oxidized by Mono amine oxidase(MAO) enzyme into DOGAL(3,4 Hydroxy phenyl glycoaldehyde) • DOGAL(3,4 Hydroxy phenyl glycoaldehyde) is metabolized into DOMA(Dihydroxy mandelic acid) by aldehyde dehydrogenase enzyme
• 14.
  Adrenergic Responses andeffects Rece ptor Location Mechanism of action Response Effect α1 Arterioles, Veins, Eye, Liver (AVIL) Influx of Ca+, Depolarization Excitatory response Vasoconstriction, Increases blood pressure, nasal decongestant α2 Salivary gland, Pancreas, GIT Sphincters, Adipose tissue, Veins, Presynaptic membrane(GAPS) Outflow of K+, Hyperpolarisation Excitatory response Vasoconstriction, Decreases insulin release, Decreases salivary secretion, Analgesic, Sedative β1 Heart, Kidney, Adipose Tissue(HAK) Activation Adenylate cyclase, Protein Kinase, Phosphorylation Inhibitory response Increases Heart rate β2 Bronchial Muscle, Arterioles, Intestine, Lung, Liver, Pancreas, Uterus. (BALLU) Activation Adenylate cyclase, Protein Kinase, Phosphorylation Inhibitory response Bronchial Muscle dilation, lipolysis β3 Urinary Bladder, Adipose Tissue (UA) Activation Adenylate cyclase, Protein Kinase, Phosphorylation Inhibitory response Dilation of urinary bladder
• 15.
  Organ wise Distributionof Adrenergic and Cholinergic receptor Organ Adrenergic Receptor Response Chonergic receptor Response Heart B1 Contraction of Heart M2 Relaxation of Heart Bronchial Smooth Muscle B2 Dilation of smooth muscle M2, M3, M4 Contraction of Smooth Muscle Kidney B2 Promotes urination M1 Inhibits urination GIT α2 Inhibits secretion M1 Promotes secretion Salivary Gland α2 Inhibits secretion M1 Promotes secretion Uterus B2 Dilation of Uterus M4 Contraction of Uterus Urinary Bladder B3 Dilation of Bladder M4 Contraction of Bladder Eye α1 Dilation of Pupils M5 Contraction of Pupils Liver B2 Promotes Glycogenolysis M3 Inhibition of Glycogenolysis Adipose Tissue B2 and B3 inhibits deposition of fats M1 Promotes Deposition of fats CNS D1&D2 Excitation in CNS M4,M5 Depression in CNS
• 16.
  Mechanism action ofCatecholamine's on B Receptors
• 17.
  Mechanism of actionof Catecholamine's on B receptor Catecholamine's binds with B receptor couples with G-Protein Activates G-Protein and dissociates, Hence GDP is converted to GTP and GTP-G-Protein complex is produced GTP and GTP-G-Protein complex bind with membrane enzyme adenylate cyclase, and activates to adenylate cyclase Adenylate cyclase metabolize the ATP into Cyclic AMP,. CAMP binds with Protein Kinase, activates protein kinase Phosphorylation, gives biological effect E.G Glycolysis in liver
• 18.
  Mechanism action ofCatecholamine's on α Receptors
• 19.
  Mechanism action ofCatecholamine's on α Receptors Epinephrine binds with α Receptor and activates Gq protein Gq protein binds with GDP to form GTP, GTP activates Phospholipase C Phospholipase c coverts PIP2 (Phosphodidyl inositol 4,5 diphosphate) into IP3 ( Inositol 1,4,5 Triphosphate) Phospholipase c coverts PIP2 (Phosphodidyl inositol 4,5 diphosphate) into IP3 ( Inositol 1,4,5 Triphosphate), it results into release calcium from sarcoplasmic reticulum, it increases level of calcium inside the cell Ca+ binds with caM (Calmodulin) and this complex activates the MLCK, MLCK(Myosin light chain kinase) phosphorylates myosin and actin will bind with phosphorylated myosin form cross bridge of actin-myosin which results into vasoconstriction and high blood pressure
• 20.
  Pharmacological actions Catecholamine's 1.They exert excitatory effects on smooth muscles present in blood vessels and salivary as well as sweat glands 2. They initiate inhibitory responses on smooth muscles of GIT, bronchial tract, blood vessels provided to skeletal muscles, thus blood vessels get dilated to supply the skeletal muscles with more blood 3. They exert excitatory effects on cardiac cells resulting into an increase in force of contraction(increases heart rate) 4. They promotes glycogenolysis in liver and skeletal muscles and reduces production of fatty acid in adipose tissue
• 21.
  Pharmacological actions Catecholamine's 5.The increased level of catecholamine's in the CNS leads to respiratory stimulation, alertness, CNS stimulation, an increase in psychomotor activity and reduction of appetite 6. Epinephrine reduces intraocular pressure and used in the treatment of glaucoma 7. The secretion of endocrine gland either decreases
• 26.
  2. Classification basedon Mechanism Of Action Direct Acting: The drug which is acted by directly binding with α1, α2, β1, and, β2 receptors is considered as direct acting e.g. Epinephrine, Nor-Epinephrine, Dopamine, Dobutamine, Isoprotinol, methyl DOPA, Clonidine, Naphazoline, Oxymetazoline, Xylometazoline, Terbutaline, Salbutamol, Bitolterol Indirect Acting: The Agent that stimulates secretion and inhibits the reuptake of adrenaline e.g. Hydroxyamphetamine, Pseudoephedrine, propyl hexidrine Mixed Acting: the agents which acted by binding with α1, α2, β1, and, β2 receptors as well as stimulate the secretion of noradrenaline and inhibit the reuptake of noradrenaline e.g. Ephedrine, Metarminol
• 28.
  A. 1.Direct ActingAdrenergic Drugs(Catecholamine) H2C HO H N OH C CH3 CH3 CH3 OH HO HO NH2 Dopamine HO HO NH2 Methyl Dopa HO HO H N Epinephrine OH CH3 1 2 4 HO HO H N Isoprenaline(Isoprotenol OH C 5 CH3 CH3 CH3 4-(2-aminoethyl)benzene-1,2-diol 4-(2-(tert-butylamino)-1- hydroxyethyl)benzene-1,2-diol 4-(1-hydroxy-2- (methylamino)ethyl)benzene- 1,2-diol Salbutamol HO H N OH CH3 Phenylephrine 7 8 3-(1-hydroxy-2- (methylamino)ethyl) phenol 4-(2-(tert-butylamino)-1-hydroxyethyl)-2- (hydroxymethyl)phenol HO HO NH2 Nor-epinephrine OH 3 4-(2-amino-1-hydroxyethyl)benzene-1,2-diol H N OH C CH3 CH3 CH3 Terbutaline 9 HO HO 5-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,3- diol H N OH C H CH3 CH2 Dobutamine 6 HO HO CH2 4-(1-hydroxy-2-(4-(4- hydroxyphenyl)butan-2- ylamino)ethyl)benzene-1,2- diol HO COOH CH3 3-(3,4-dihydroxyphenyl)-2-methyl- 2-(amino)propanoic acid
• 29.
  A. 1.Direct ActingAdrenergic Drugs(Catecholamine) O O CH C H2 NH C CH3 CH3 CH3 OH C C O O Bitolterol(Bronchodilator inasthm& COPD) 4-(1-hydroxy-2-tert-butylamino-ethyl) -2-(4-methyl benzoyl)-phenyl)4-methyl benzoate 10.
• 30.
  A.2. Direct ActingAdrenergic Drugs (imidazoline ring) NH N H N Cl Cl Clonidine(antihyper tensive, Antigrane) N-(2,6-dichlorophenyl)-4,5-dihydro-1H- imidazol-2-amine NH N H N Naphazoline (Nasal deconstant) N-(naphthalen-1-yl)-4,5-dihydro-1H-imidazol-2-amine 1 2 NH N H2 C H3C H3C Oxymetazoline 3 OH C CH3 CH3 CH3 6-tert-butyl-3-((4,5-dihydro-1H-imidazol-2-yl)methyl)-2,4- dimethylphenol NH N H H2 C H3C H3C Xylmetazoline 4 C CH3 CH3 CH3 2-(4-tert-butyl-2,6-dimethylbenzyl)imidazolidine
• 31.
  B. Indirect ActingAdrenergic Drugs HO CH2 H C CH3 NH2 Hydroxy Amphetamine (Dllate the pupils) 4-(2-aminopropyl)phenol CH H C CH3 H N Pseudoephedrine, (Hypertensive, nasal decongestant) OH CH3 2-(methylamino)-1-phenylpropan-1-ol H2 C H C NH CH3 CH3 Propyl hexeridine Nasal Deconstestant, Psychostimulant 1-cyclohexyl-N-methylpropan-2-amine 1 2 3
• 32.
  C. Mixed ActingAdrenergic Drugs H C C H H N Ehedrine, (Hypertensive, nasal decongestant) CH3 2-(methylamino)-1-phenylpropan-1-ol OH CH3 H C C H H N Metarminol (hypertensive, nasal decongestant) CH3 OH CH3 OH 3-(1-hydroxy-2-(methylamino)propyl)phenol
• 33.
  3. Classification basedon Receptor Selectivity 1. α1 Agonist: Phenylephrine, Naphazoline, Oxymetazoline, Xylometazoline, Methoxamine, Midodrine 2. α2 Agonist: Clonidine, Gaunabenz, Guanfacin, Epinephrine, Tizanidine, brimonidine, apraclonidine 3. α1& α2 Agonist: Epinephrine, Norepinephrine 4. β1 Agonist: Isoprotinol, Dobutamine 5. β2 Agonist: Terbutaline, Salbutamol 6. β1 and β2 agonist: Adrenaline, Isoprotinol, Dobutamine 7. α and β Agonist: Adrenaline, Ephedrine
• 34.
  4. Classification basedon Therapeutic effect 1. Vasoconstrictor: Adrenaline, Nor adrenaline, Metarminol, ephedrine 2. Vasodilator: Dopamine and Isoprenaline 3. Bronchodilator: Salbutamol, Terbutaline 4. CNS Stimulant: Amphetamine, Methamphetamine 5. Cardiac Stimulant: Adrenaline, Isoprenaline 6. Nasal Decongestant: Naphazoline, Oxymetazoline 7. Uterine relaxant: Salbutamol, Nylidrine
• 36.
  S.A.R. Of Catecholamine's A.Substitution at Aromatic /phenyl Ring B. Substitution at α carbon atom C. Substitution at β Carbon atom D. Substitution at Amino group
• 37.
  H C H C H N R2 OH HO HO a ß R1 3-OH moreimportant a activity 4-OH More important for ß actvity R2 Substitution ß Activity a Actvity Branching in alky chain (tert. butyl) ß Activity degradation by MAO R1 Substitution 1. Methyl substituents decreases MAO degradation 2. ethyl substituents decreases a actvity compared ß(increases ß selectvity) 3. Ethyl group increases CNS Activity 4.Ethyl group increases oral activity Armotic Substitution 1. No substitution decreses activity 2. both hydroxyl requires for a and ß agonist action 3. Easily metabolised by COMT 4. Decreases duration of action and oral activity 5. Decreases CNS Activity Position of OH Group and substitution 1. 3,5 OH group increses ß selectivity 2. CH2OH, 4OH-increses ß selectivity 3. Decreses degradation by COMT 4. Increases oral and duration of action Structure Activity Relation ship of Catecholamines
• 39.
  A. Substitution atAromatic ring 1. The presence of OH group in the benzene ring at 3,4 positions gives maximum α and β activity. If any of these OH group is absent, the overall potency gets decreased e. g Phenylephrine is less potent than adrenaline HO HO H N CH3 OH HO H N CH3 OH Phenylephrine (Less Potent) Epinephrine (More Potent) 2. The presence of OH Group at 3,5 Position(resorcinol) with bulky substituent's on the amino nitrogen gives β2 selective e. g Terbutaline relaxes bronchial muscle without affecting on cardiac muscles HO H N C OH HO CH3 CH3 CH3 Terbutaline(B2 agonist) (Bronchodilator)
• 40.
  A. Substitution atAromatic ring 3. Drugs having substituent's other than OH groups having greater selectivity for B2 Adrenoreceptors e.g. salbutamol is β2 selective( Bronchodilator) 4. Unsubstituted or Alkyl substituted adrenergic amines easily crosses the blood brain barrier and have more CNS Activity e. g Amphetamine and Ephedrine HOH2C HO H N C OH Salbutamol (ß2 Selective) CH3 CH3 CH3 H N OH CH3 Ephedrine NH2 OH CH3 Amphetamine CH3
• 41.
  A. Substitution atAromatic ring 5. 2′,5′-dimethoxy substitution of methoxamine, which is a selective α-agonist that also has β-blocking activity at high concentrations NH2 OH CH3 OCH3 OCH3 Methoxamine (alpha agonist)
• 42.
  B. Substitution αCarbon atom 1. Drugs having substituent's on the α Carbon atom blocks the metabolism caused by MAO and hence these have longer duration of action e. g Amphetamine resist degradation by MAO 2. Methyl or ethyl group substitution on α Carbon atom reduces direct receptor agonist activity NH2 Amphetamine CH3 H N CH3 CH3 OH Ephedrine(Less Potent H N CH3 OH Epinephrine(More motent
• 43.
  C. Substitution βCarbon atom NH2 Amphetamine(More CNS Acivity) CH3 H N Ephedrine(Less CNS Activity) CH3 CH3 OH C. Substitution Carbon atom β carbon atom 1. OH group on the β carbon atom decreases Central stimulant action due to lower lipid solubility of drug(OH gives polar effect) e. g Ephedrine has less CNS activity than amphetamines 2. OH Group at β carbon atom is essential for adrenergic activity
• 44.
  D. Substitution atAmino Group 1. Lesser substitution on the amino group, higher will be selectivity for α receptors. Adrenaline is highly α selective than nor adrenaline. 2. More the size of alkyl substituent's, higher will be β2 selective action. e.g. Terbutaline and Salbutamol have selective β2 activity HO HO H N CH3 OH Epinephrine (lessalpha selctive) HO HO NH2 OH Nor-epinephrine (More alpha selctive) HOH2C HO H N C OH Salbutamol (ß2 Selective) CH3 CH3 CH3 HO H N C OH HO CH3 CH3 CH3 Terbutaline(B2 agonist) (Bronchodilator)
• 45.
  D. Substitution atAmino Group 3. Catechol Ring must be separated from amino by ethylene bridge HO HO H N CH3 OH Epinephrine (lessalpha selctive) HO HO NH2 OH Nor-epinephrine (More alpha selctive) 4. Primary and secondary amines are more potent direct acting agonist than 3° and 4° amines
• 46.
  S.A.R of NonCatecholamine's Bridging Unit: A single Unit of the Methylene or Amino group is essential for agonist activity a) If CH2 is the Bridging unit then it shows α1 Agonist activity e.g. Oxymetazoline b) If NH is a bridging unit then it shows α2 agonist activity e. g clonidine Imidazoline Ring: Imidazoline ring shows more affinity to α receptor and any substitution at Imidazoline ring decreases α adrenergic activity Replacement of Imidazoline with Oxazolidinone ring decreases its potency e.g. relminidine is less potent than clonidine. Aromatic Ring: a) Substitution at the Aromatic ring by the alkyl group enhances adrenergic activity e.g. Oxymetazoline b) Substitution at the Aromatic ring by the halogen group enhances adrenergic activity e.g. clonidine c) Substitution at the aromatic ring by the hydroxyl group enhances adrenergic activity X N HN Bridging Unit Imidazoline Ring Aromatic Ring O N H N rilmenidine NH N H N Cl Cl Clonidine(a2 agonist ) NH N H2 C H3C H3C Oxymetazoline(a1 agonist) OH C CH3 CH3 CH3
• 47.
  Synthesis of Phenylephrine Selectiveα1 Agonist Phenylephrine increases the blood pressure by vasoconstriction It is used as a local decongestant HO H2 C Cl Cl O Chloro acetyl Chloride AlCl3 HO H2 C Cl O -HCl CH3-NH2 HOH2C HO H2 C N H O HOH2C HO H2 C N H OH CH3 MPV Red CH3 Phenol Phenylephrine
• 48.
  HOH2C HO H2 C Cl Cl O Chloro acetyl Chloride 2-HydroxyBenzyl alcohol AlCl3 HOH2C HO H2 C Cl O -HCl (CH3)3C-NH2 HOH2C HO H2 C N H O C CH3 CH3 CH3 HOH2C HO H2 C N H OH C CH3 CH3 CH3 MPV Red Salbutamol Synthesis of Salbutamol Selective B2 Agonist It is a Bronchodilator and choice of the drug in the treatment of Bronchial Asthma
• 54.
  N H N H3COOC OH Yohimbine Alpha 2 Blockers
• 55.
  Miscellaneous class ofAlpha Blockers N N O NH C O N NH H R O H HO O Dihydro ergotamine Used in migrane vein thrombosis vasocnonstrictor N N H N OH CH3 CH3 H H CH3 H O Methyl sergide Anti-migrane oxytocic vasoconstrictor N-(1-hydroxybutan-2-yl)-4,7-dimethyl- 4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide
• 62.
  1. Non selectivebeta Blocker O H2C C H OH CH2 NH CH CH3 CH3 H3C CH3 O CH3 C O CH3 Metipralol Non selective b blocker membrane stabiliser 4-(2-hydroxy-3-(isopropylamino)propoxy)-2,3,6-trimethylphenyl acetate
• 64.
  OH C CH2 OH O NH2 NH CH CH3 CH2 CH2 2-hydroxy-5-(1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl)benzamide Labetalol(antihypertensive) antihypertensive HN O H2 C C H OH CH2 NH CH2 CH2 O H3CO Carvedilol( Anti-CHF, Antihypertensive 4-(9H-carbazol-4-yloxy)-1-(2-(2-methoxyphenoxy)ethylamino)butan-2-ol Non selective Alpha plus beta Blocker
• 65.
  Selective Alpha plusbeta Blocker O CH2 CH2 OCH2 CH2 C H OH CH2 NH CH CH3 CH3 Betazolol Anti-hypertensive Anti-gloucoma