Dr. ISHOLA I.O. PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY CMUL 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 α and β 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 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 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 α1 mediate the contraction of arterial and venous smooth muscle α2 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 α1 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’d α2 control peripheral and central Activation of α2 inhibit the release of NA from Psympathetic nerve endings Blockade 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 Non-selective Phenoxybenzamine, Phentolamine ALPHA BLOCKERS: Non-selective Phenoxybenzamine, Phentolamine Alpha -1 selective Prazosin, Terazosin, Tamsulosin Alpha-2 selective Yohimbine Tamsulosin ( Flomax)

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 2 N Norepinephrine NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response a1 adrenergic receptor

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

Clinical pharmacology of a-adrenergic receptor antagonists Route of Drug Receptor admin. Clinical uses Phenoxybenzamine a , a Oral Pheochromocytoma, hypertensive crisis 1 2 Phentolamine a , a Parenteral Pheochromocytoma, hypertensive crisis, 1 2 male impotence Prazosin a Oral Hypertension, benign prostatic 1 hypertrophy Terazosin a Oral Hypertension, benign prostatic 1 hypertrophy Doxazosin a Oral Hypertension, benign prostatic 1 hypertrophy Side effects of a1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

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

Non-selective adrenergic receptor antagonists b-Haloalkylamines Non-selective a receptor antagonist Also blocks acetylcholine, histamine, and serotonin receptors Irreversible antagonist resulting from covalent modification of receptor Phenoxybenzamine (Dibenzyline)

Non-selective adrenergic receptor antagonists b-Haloalkylamines: Mechanism of receptor inactivation receptor alkylated receptor

Non-selective adrenergic receptor antagonists Imidazolines 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 Phentolamine (Regitine)

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

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 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 Yohimbine (Yocon)

b-adrenergic receptor antagonists Aryloxypropanolamines Note: non-carbon atom in side chain

b-adrenergic receptor antagonists Non-selective Lipophilic Local 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 Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine Nadolol (Corgard) Thiadiazole nucleus with morpholine ring Administered: Oral, Ophthalmic Uses: Hypertension, angina, migraine, glaucoma Timolol (Timoptic, Blocadren) How will -blockers affect pupil size?

Non-selective b-adrenergic receptor antagonists Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral Uses: Hypertension, angina, migraine Pindolol (Visken) 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 “Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina Atenolol (Tenormin)

Selective b1-adrenergic receptor antagonists 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 Esmolol (Brevibloc)

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+ MAO DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

Effect of chronic b-receptor blockade: Receptor up-regulation Na+ Tyrosine Na+ Dopamine Tyrosine Action Potential H+ MAO DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

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 Non-selective b receptor antagonist a1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses b-blocking activity (1S, 1’R)-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 Labetalol (Normodyne, Trandate)

Mixed adrenergic receptor antagonists Carvedilol (Coreg) Non-selective b receptor antagonist a1 receptor antagonist Both enantiomers antagonize a1 receptors Only (S)-enantiomer possesses b-blocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure (Types II and III)

1 2 3 Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2 Action Potential H+ MAO DA NE NE Ca2+ Uptake 1 3 Na+, Cl- NE NE NE NE b Effector organ

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

Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Tyrosine Reserpine Guanethidine Action Potential H+ MAO NE NE Ca2+ NE Guanethidine, Bretylium Guanethidine b Effector organ

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

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)

Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Guanethidine Tyrosine Action Potential H+ MAO NE NE Ca2+ NE Guanethidine, Guanethidine b Effector organ

Drugs that reduce storage or release of NE 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)

OBRIGADO