Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist - PowerPoint Presentation

Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist and Neurone blockers Dr. ISHOLA I.O. PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY CMUL

INTROPhenylethylamine can viewed as parent compound, NA, AD, DA, ISOP posesss OHO-dihydroxybenzene known as catecholDirectly acting sympathomimetic drugs influence both α and β receptors

SARSeparation 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 amineSubstitution 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 reduceCompouns without one or both hydroxyl substituents are not acted upon by COMT and their oral effectiveness and duration of action prolongedMethoxy substituents at 2 and 5 has highly selective alpha stimulating activity and large doses block beta-receptorsAlbuterol is exempted

SARSubstitution 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 isomersLevo-substitution on beta-carbon confers the greater peripheral activity; L-ADR and L-NA 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 ANTAGONISTDrugs interfere with function of the SNS and thus profound effects on the physiology of sympathetically innervated organsAdrenergic 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 antagonistsα1 mediate the contraction of arterial and venous smooth muscleα2 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 α 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

Cont’dα2 control peripheral and central Activation of α 2 inhibit the release of NA from Psympathetic nerve endingsBlockade of α2 increase SNS outflow and potentiate the release of NA from nerve endings leading to activation of α1 and B1 receptors in the heart

Adrenergic receptor agonist/antagonist

Adrenergic agonist/antagonist

Adrenergic System ALPHA BLOCKERS: Non-selective Phenoxybenzamine, PhentolamineAlpha -1 selective Prazosin, Terazosin, TamsulosinAlpha-2 selective Yohimbine

Adrenergic SystemBETA BLOCKERS: Non selective : Propranolol, Nadolol, Timolol With Partial agonist : PindololBeta 1 selective : Atenolol, MetoprololBeta and alpha 1 blocker : Labetolol, Carvedilol

Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible

NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response Receptor agonists activate signal transduction pathways a 1 adrenergic receptor H O H O C H O H C H 2 N H 2 Norepinephrine

Receptor antagonists block agonist binding to the receptor NH 3 COOH G q Phospho - lipase C Antagonist H O H O C H O H C H 2 N H 2 Norepinephrine What effect would an antagonist alone have on receptor activation?

Clinical pharmacology of a -adrenergic receptor antagonists Drug Receptor Route of admin. Clinical uses Side effects of a 1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia Phenoxybenzamine a 1 , a 2 Oral Pheochromocytoma, hypertensive crisis Phentolamine a 1 , a 2 Parenteral Pheochromocytoma, hypertensive crisis, male impotence Prazosin a 1 Oral Hypertension, benign prostatic hypertrophy Terazosin a 1 Oral Hypertension, benign prostatic hypertrophy Doxazosin a 1 Oral Hypertension, benign prostatic hypertrophy

Non-selective adrenergic receptor antagonists b -Haloalkylamines R= aromatic, alkyl X= Cl - , Br - , etc.

b -Haloalkylamines 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 receptor alkylated receptor Non-selective adrenergic receptor antagonists

Imidazolines Phentolamine (Regitine) Non-selective a receptor antagonist Competitive (reversible) blocker Potent vasodilator, but induces pronouced reflex tachycardia Block of presynaptic a 2 receptors may promote release of NE Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist Non-selective adrenergic receptor antagonists

Reversible vs. Irreversible receptor blockade 1 M Phent + Phentolamine + Phenoxybenzamine 10 M Phent 1 M Phenox 10 M Phenox

a1 -adrenergic receptor antagonists “Quinazolines” Vary in half-life: Prazosin 3 hrs Terazosin 12 hrs Doxazosin 20 hrs Undergo extensive metabolism, excreted mainly in the bile Vasodilators Relaxation of smooth muscle in enlarged prostate and in bladder base “First-dose” effect

Other a adrenergic receptor antagonists Ergot alkaloids 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 Yohimbine (Yocon) Indole alkaloid Found in Rubaceae and related trees. Also in Rauwolfia Serpentina . Blockade of a 2 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

b -adrenergic receptor antagonists Non-selective LipophilicLocal anesthetic properties Blockade is activity-dependent P r o p r a n o l o l ( I n d e r a l )

b -adrenergic receptor antagonists 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 P r o p r a n o l o l ( I n d e r a l ) 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 antagonists Thiadiazole nucleus with morpholine ringAdministered: Oral, Ophthalmic Uses: Hypertension, angina, migraine, glaucoma Timolol (Timoptic, Blocadren) Nadolol (Corgard) Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine How will -blockers affect pupil size?

Non-selective b -adrenergic receptor antagonists 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 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 “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 Atenolol (Tenormin) “Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina

Selective b1 -adrenergic receptor antagonists Esmolol (Brevibloc) 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

Action Potential Na + Effect of chronic b -receptor blockade Presynaptic neuron H + Effector organ Ca 2+ Na + Tyrosine Tyrosine Dopamine DA NE Uptake 1 Na + , Cl - NE NE NE NE NE MAO

Action Potential Na + Effect of chronic b -receptor blockade: Receptor up-regulation H + Effector organ Ca 2+ Na + Tyrosine Tyrosine Dopamine DA NE Uptake 1 Na + , Cl - NE NE NE NE NE MAO

Side effects of b -blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndromeContraindications:Asthma, COPD, congestive heart failure (Type IV)

Mixed adrenergic receptor antagonists Labetalol (Normodyne, Trandate) Non-selective b receptor antagonist a 1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses b -blocking activity (1S, 1’R)-isomer possesses greatest a 1 receptor blocking activity b -blocking activity prevents reflex tachycardia normally associated with a 1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis

Mixed adrenergic receptor antagonists Carvedilol (Coreg) Non-selective b receptor antagonist a 1 receptor antagonist Both enantiomers antagonize a 1 receptors Only (S)-enantiomer possesses b -blocking activity b -blocking activity prevents reflex tachycardia normally associated with a 1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure (Types II and III)

Action Potential Na + Pharmacologic manipulation of the adrenergic system Presynaptic neuron H + Effector organ Ca 2+ Na + Tyrosine Tyrosine Dopamine DA NE Uptake 1 Na + , Cl - NE NE NE NE b NE MAO 1 2 3

Inhibition of norepinephrine synthesis H O C H 2 C H N H 2 H O H O C H O H C H 2 N H C H 3 H O H O C H O H C H 2 N H 2 C O O H H O C H 2 C H N H 2 C O O H H O H O H O C H 2 C H 2 N H 2 T Y R O S I N E D O P A D O P A M I N E N O R E P I N E P H R I N E E P I N E P H R I N E t y r o s i n e h y d r o x y l a s e a r o m a t i c L - a m i n o a c i d d e c a r b o x y l a s e d o p a m i n e b - h y d r o x y l a s e p h e n y l e t h a n o l a m i n e - N - m e t h y l t r a n s f e r a s e Metyrosine X

Action Potential Na + Drugs that reduce storage or release of NE H + Effector organ Ca 2+ Na + Tyrosine Tyrosine Dopamine NE NE b NE MAO Reserpine Guanethidine Guanethidine Guanethidine, Bretylium

Catecholamine depleters Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension May precipitate depression Reserpine (Serpasil) Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE

Drugs that reduce storage or release of NE 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 Guanethidine (Ismelin)

Action Potential Na + Drugs that reduce storage or release of NE H + Effector organ Ca 2+ Na + Tyrosine Tyrosine Dopamine NE NE b NE MAO Guanethidine Guanethidine Guanethidine,

Drugs that reduce storage or release of NE Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent further release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular fibrillation) Bretylium tosylate (Bretylol)

OBRIGADO