Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist and Neurone blockers DR. ISHOLA I.O. PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY CMUL INTRO Phenylethylamine can viewed as parent compound, NA, AD, DA, ISOP posesss OH O-dihydroxybenzene known as catechol Directly acting sympathomimetic drugs influence both and receptors SAR Separation of aromatic and amino group greatest sympathomimetic activity occurs when two carbon atoms separate the ring from amino group (DA, NA, AD etc)
Substitution on the amino group- increase in the size of alkyl substituents increases beta-receptor activity (isoprenaline) and vice versa, N-methylation increase the potency of primary amine Substitution on the aromatic nucleus- maximal alpha and beta activity depends on the presence of hydroxyl groups on position 3 and 4. oH-on position 3 and 5 confers beta receptor selectivity on compounds with large amino substituents (terbutaline, metaproterenol- relax bronchial smooth muscle but less cardiac stimulation, when absent potency reduce Compouns without one or both hydroxyl substituents are not acted upon by COMT and their oral effectiveness and duration of action prolonged Methoxy substituents at 2 and 5 has highly selective alpha stimulating activity and large doses block beta-receptors Albuterol is exempted SAR
Substitution on the alpha-carbon atom- this substitution block oxidation by MAO (EPHEDRINE OR AMPHETAMINE), thus prolonging the duration of action Substitution on the beta-carbon atom- Substitution of a hydroxyl group on the beta carbon generally decreases action within the CNS largely because it lowers lipid solubility but enhances agonist activity at both alpha and beta adrenergic receptor, ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing BP and HR Optical isomerism- substitution on either alpha or beta carbon yields optical isomers Levo-substitution on beta-carbon confers the greater peripheral activity; L-ADR and LNA are 10X AS POTENT as their unnatural D-isomers; D-sub on alpha = more potent compound- D-AMP more potent than L-amp in central but not peripheral SAR ADRENERGIC RECEPTOR ANTAGONIST Drugs interfere with function of the SNS and thus profound effects on the physiology of sympathetically innervated organs
Adrenergic antagonist inhibit the interaction of NA,AD, and other sympathomimetic drugs with adrenergic receptors All the ADR antagonists bind competitively except phenoxybenzamine (covelent) Alpha adrenergic antagonists 1 mediate the contraction of arterial and venous smooth muscle 2 involved in suppressing sympathetic output, increasing vagal tone, facilitate platelet aggregation and inhibit the release of NA and Ach from nerve endings and regulate metabolic effects Blockade of 1 receptors inhibit vasocontraiction = vasodilation in both arterial and veins = decrease in PVR = fall in BP (opposed by baroreceptor reflexes) Activity
less in supine than upright position Contd 2 control peripheral and central Activation of 2 inhibit the release of NA from Psympathetic nerve endings Blockade of 2 increase SNS outflow and potentiate the release of NA from nerve endings leading to activation of 1 and B1 receptors in the heart Adrenergic receptor agonist/antagonist Adrenergic agonist/antagonist Adrenergic System ALPHA BLOCKERS: Non-selective
Phenoxybenzamine, Phentolamine Alpha -1 selective Prazosin, Terazosin, Tamsulosin Alpha-2 selective Yohimbine Adrenergic System BETA BLOCKERS: Non selective : Propranolol, Nadolol, Timolol With Partial agonist : Pindolol Beta 1 selective : Atenolol, Metoprolol Beta and alpha 1 blocker : Labetolol, Carvedilol Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist
Reversible vs. Irreversible Receptor agonists activate signal transduction pathways HO NH3 HO CH CH2 NH2 OH Norepinephrine a1 adrenergic receptor Gq (+) Phospho- lipase C
PIP2 COOH IP3 Diacylglycerol Increase Ca2+ Activate Protein Kinase C Response Receptor antagonists block agonist binding to the receptor HO HO Antagonist CH2 NH2 OH NH3
Norepinephrine Gq What effect would an antagonist alone have on receptor activation? CH COOH Phospholipase C Clinical pharmacology of a-adrenergic receptor antagonists Drug Phenoxybenzamine Phentolamine Route of Receptor admin. Clinical uses a1, aa2 a1, aa2 Prazosin a1
R N CH2 CH2 R R= aromatic, alkyl X= Cl-, Br-, etc. X Non-selective adrenergic receptor antagonists b-Haloalkylamines CH3 O N Cl Phenoxybenzamine (Dibenzyline) Non-selective a receptor antagonist Also blocks acetylcholine, histamine, and serotonin receptors
Irreversible antagonist resulting from covalent modification of receptor Non-selective adrenergic receptor antagonists b-Haloalkylamines: Mechanism of receptor inactivation R R R N N R Cl- R Cl- R N Nu Cl Aziridinium ion receptor
R R N Nu alkylated receptor Non-selective adrenergic receptor antagonists Imidazolines HO N N CH2 N H H3 C Phentolamine (Regitine) Non-selective a receptor antagonist Competitive (reversible) blocker
Potent vasodilator, but induces pronouced reflex tachycardia Block of presynaptic a2 receptors may promote release of NE Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist 1 M Phent 100 50 10 M Phent 0 -10 -8 -6 -4 Log [Norepinephrine] + Phentolamine
a Adrenergic 1 receptor activation a Adrenergic 1 receptor activation Reversible vs. Irreversible receptor blockade 100 1 M Phenox 50 0 10 M Phenox -10 -8 -6 -4
Log [Norepinephrine] + Phenoxybenzamine a1-adrenergic receptor antagonists Quinazolines O Quinazoline ring N H3CO N R Acyl moiety N N Prazosin 3 hrs Terazosin 12 hrs
Doxazosin 20 hrs Undergo extensive metabolism, excreted mainly in the bile Piperazine ring H3CO Vary in half-life: Vasodilators Relaxation of smooth muscle in enlarged prostate and in bladder base NH2 First-dose effect Prazosin: R = (Minipres) Terazosin: R = (Hytrin) Doxazosin: R = (Cardura)
O O O O Other aa adrenergic receptor antagonists Ergot alkaloids O R' N O N R O NH O NCH3 N
H Derivatives of Lysergic Acid Product of the grain fungus Claviceps purpura 5 Major alkaloids based on R and R; Ergotamine the most common Used in the treatment of migraine Ergots possess strong oxytocic action a2-adrenergic receptor antagonists N N H H H H H3CO2C Yohimbine (Yocon) OH
Indole alkaloid Found in Rubaceae and related trees. Also in Rauwolfia Serpentina. Blockade of a2 receptors increases sympathetic discharge Folklore suggests use in the treatment of male impotence b-adrenergic receptor antagonists Aryloxypropanolamines Note: non-carbon atom in side chain O Ar NH R OH Ar = aromatic ring structure R = bulky alkyl group (isopropyl or tert-butyl) b-adrenergic receptor antagonists
CH3 O OH Propranolol (Inderal) N H CH CH3 Non-selective Lipophilic Local anesthetic properties Blockade is activitydependent
b-adrenergic receptor antagonists CH3 O OH Propranolol (Inderal) N H CH Pharmacological effects Decreased cardiac output and heart rate Reduced renin release Increase VLDL, Decrease HDL
Inhibit lipolysis Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia Increase bronchial airway resistance CH3 Therapeutic uses for b-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III) Non-selective b-adrenergic receptor Less lipophilic than propranolol CH3 antagonists Long half-life: ~20 hours O HO
OH N H CH CH3 HO Nadolol (Corgard) CH3 O O OH N N H C
CH3 CH3 N N S Timolol (Timoptic, Blocadren) Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine Thiadiazole nucleus with morpholine ring Administered: Oral, Ophthalmic Uses: Hypertension, angina,
migraine, glaucoma How will b-blockers affect pupil size? Non-selective b-adrenergic receptor antagonists CH3 O OH N H CH CH3 N H Pindolol (Visken)
Possesses Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral Uses: Hypertension, angina, migraine What would a pindolol dose-response curve look like? Non-selective b-adrenergic receptor antagonists CH3 O OH N C CH3 H CH3 O N
H Carteolol (Cartrol, Ocupress) Possesses Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma Selective b1-adrenergic receptor antagonists CH 3 O OH N H CH CH3 R Metoprolol (Lopressor, Toprol)
R= CH2 O CH3 CH3 Bisoprolol (Zebeta) CH R= O CH2 CH2 O CH3 Cardioselective Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic, congestive heart failure Selective b1-adrenergic receptor
antagonists CH3 O OH N H CH NH2 O Atenolol (Tenormin) CH3 Cardioselective Less bronchconstriction Low lipophilicity Half-life: 6-9 hours
Administered: Oral, parenteral Uses: Hypertension, angina Selective b1-adrenergic receptor antagonists CH3 O N H OH CH O O CH3 Esmolol (Brevibloc) CH3 Very short acting Half-life: 9 minutes Rapid hydrolysis by esterases found in red blood cells Administered: Parenteral
Note: incompatible with sodium bicarbonate Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Effect of chronic b-receptor blockade Na+ Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine Action Potential H+ O MA
DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE Effector organ NE Effect of chronic b-receptor blockade: Receptor up-regulation Na+ Tyrosine Na+ Dopamine Tyrosine
Action Potential H+ O MA DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE Effector organ NE Side effects of b-blockers:
Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Contraindications: Asthma, COPD, congestive heart failure (Type IV) Mixed adrenergic receptor antagonists OH 1 H N 1' CH3 HO CONH 2 Labetalol (Normodyne, Trandate) Non-selective b receptor antagonist a1 receptor antagonist Two asymmetric carbons (1 and 1) (1R, 1R)-isomer possesses bblocking activity (1S, 1R)-isomer possesses
greatest a1 receptor blocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis Mixed adrenergic receptor antagonists OCH3 O OH N H N H O Carvedilol (Coreg) Non-selective b receptor antagonist a1 receptor antagonist Both enantiomers antagonize a1 receptors
Only (S)-enantiomer possesses bblocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure (Types II and III) Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2
Action Potential H+ O MA DA NE NE Ca2+ NE NE 3 NE Effector organ Uptake 1 Na+, Cl- NE b
HO CH2 CH NH2 TYROSINE COOH Inhibition of norepinephrine synthesis HO HO X tyrosine hydroxylase Metyrosine CH2 CH NH2 DOPA
COOH aromatic L-amino acid decarboxylase HO HO CH2 CH2 NH2 DOPAMINE dopamine b -hydroxylase HO HO CH CH2 NH2 NOREPINEPHRINE OH phenylethanolamineN-methyltransferase HO HO CH
OH CH2 NH CH3 EPINEPHRINE Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Reserpine Guanethidine Action Potential Tyrosine O MA H+ NE NE
Ca2+ NE Guanethidine, Bretylium Effector organ Guanethidine b Catecholamine depleters N H3CO N H H H O OC H H3CO2C
OCH3 Reserpine (Serpasil) Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE OCH3 OCH3 OCH3 Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension
May precipitate depression Drugs that reduce storage or release of NE N H N C NH2 NH Guanethidine (Ismelin) Possess guanidino moiety (pKa > 12) Resonance stabilization of cation spreads
positive charge over the entire four atom system Almost completely protonated at physiological pH Pharmacologic sympathectomy Effects can be blocked by transport blockers Uses: Hypertension Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Tyrosine Guanethidine
Action Potential O MA H+ NE NE Ca2+ NE Guanethidine, Effector organ Guanethidine b Drugs that reduce storage or release of NE CH3 CH N CH2CH3
O3S CH3 Br Bretylium tosylate (Bretylol) Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent further release (depletion) Local anesthetic Administered: Parenteral
Uses: Antiarrhythmic (ventricular fibrillation) CH3 OBRIGAD O
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