Introduction

-Blockers Antagonists -Blocker Uses

Treat stable (exercise-induced) angina Unstable Angina Hypertension Myocardial infarction Arrhythmias Gluacoma Tremors Migraine headaches Counteract detrimental effects of sympathetic nervous system activation in heart failure - Started at low doses & slowly & gradually increased

-Blockers Antagonists have either or blocking activity Some (Labetolol) -Blockers Anagonists have BOTH & blocking activity or action Due to structural modifications are selective for a particular receptor subtype Some -blocker antagonists (Pindolol & Acebutolol) with Intrinsic Sympathomimetic Activity (ISA) at the -receptor partial agonists w/ some "background" of sympathetic activity while preventing normal and enhanced sympathetic activity

Structure allows classification into the 4 sub-classes 1. Non-selective -adrenergic antagonists 2. Selective (1) at LOW dosesat therapeutic doses much of the selectivity is lost 3. antagonists with 1 receptor blocking activity Labetolol & Carvedilol 4. Those with ISAPindolol (carteolol & acebutolol to a less degree) PHARMACOPHORE

ArylETHANOLamine Aryl (Aromatic) X = NOTHING Ethanol = an ethyl w/an alcohol functional group Amine = NH2 LACKS features for agonistic activity (catechol) ALL are NON-Selective

ArylOXYpropanolamine Aryl (Aromatic) X = methoxy (CH2O-) Ethanol = an ethyl w/an alcohol (C2) functional group Amine = NH2 LACKS features for agonistic activity (catechol) More POTENT than arylethanolamines - Make up a MAJORITY of -antagonists 1 SELECTIVE = ArylOXYpropanolamine w/-directing group on NH w/ para substituent with or without Ortho substituent Stereochemistry - S isomer is approximately 100x more POTENT than R isomer

SAR R-Group -DIRECTING groups-- I-propyl; t-butyl ; Aromatic N ESSENTIAL for ANCHORING alkyl/aralkyl Side Chain (ethyl group) Carbinol Carbon (C-OH) = ASSYMETRIC center Optimal stereochemistry depends on X & determines selectivity Arylethanolamine if X=H optimal is R Aryloxypropanolamine optimal is S Arylethanolamine Determining stereochemistry NON-Selective 1 & 2 - Number each substituent by molecular weight ( #1= highest & #4 Aryloxypropanolamine lowest) SELECTIVE 1 - Connect the dots to find rotation R=Right S=Left Ar (Aromatic Ring) May affect the ADME of -antagonists May be responsible for ISA & Selectivity at 1 receptors Ar = PHENYL on ArylOXYpropanolamine Non-substituted phenyl = NON-Selective -antagonism PARA substituent = 1 selectivity Specific SAR requirement for 1 selectivity on arylOXYpropanolamine is PARA substituent on phenyl & directing group on anchoring amino Chemical Nature of para substituent does NOT influence selectivityAFFECTS POTENCY Potency is affected if para substituent is CONJUGATED w/ aromatic ring Conjugation allows resonance potency requiring more drug to elicit a therapeutic effect Ortho substituents along with para maintains 1 Selectivity (Example: Acebutolol (image below) Lipophilic nature of groups impact overall PENETRATION into CNS = CNS side effects carbon chain length & cyclopropyl groups Ar = Naphtyl-

Aromatic ring other than phenyl = NON-selective HIGHLY Lipophilic penetration of BBB Contributes to first pass effect = DOA Detrimental to compliance Lipophilicity is important consideration for topical ophthalmic drugs for treatment of glaucoma - Highly Lipophilic become EMBEDDED in the membrane & do NOT have systemic distribution - Lower concentrations are neededbenefits if a patient has COPD or Asthma (wont stimulate other receptorsMore selective) - LESS lipophilic drugs (especially non-selective) will have potential adverse effects on the lungs in patients with lung diseases (COPD, Asthma) -

Nadolol Naphthyl saturated w/ -OH @ META positions Hydroxyls Polarity & CNS Penetration = Less side effects more compliant Polarity = less liver metabolism & excretion via Kidneys LONGER DOA **NOTE: HIGHLY Polar drugs have DOA b/c they are readily excreted by the kidneys Nadolol has BOTH Lipophilicity & Polarity = Intermediate lipophilicity = DOA** Drugs w/ HIGH lipophilic nature have first pass effect = DOA Drugs w/HIGH Polarity kidney excretion = DOA

Ar = Indole or Thiazidiazole

Trandate or Labetalol

Propranolol

Indole is thought to contribute to ISA through H-Bonds interaction between mheteroamtom (N1 nitrogen atom) & SER of - receptors - -antagonists with ISA are GOOD CHOICE for HTN in patient w/ bradycardiaCan STIMULATE heart too. - -antagonists with ISA are a GOOD CHOICE to treat HTN in patients w/Hyperlipidemia LIPID NEUTRAL do NOT Triglycerides or HDL = GOOD CHOICE for patients w/ HYPERLIPIDEMIA UNIQUE SAR - Arylethanolamine w/ -directing ARALKYL Similar to peripheral 2 agonists Contributes to SOME 2 agonists in the periphery = Vasodilation & BP - Arylethanolamine = NON-selective -blocker = BP due to blocking of 1 receptors on the heart (contractility etc.) - TWO asymmetric carbons = 4 Isomers (SS, SR, RS,RR) Marketed as a Racemic Mixture RR isomer = NON-selective antagonism SR isomer = 1 antagonism (vasodilation) - 3 structural features (aralkyl, RR isomer, SR Isomer)POTENT decrease in BP - 1 antagonism activity may contribute to FAVORABLE effects on lipid profile w/no HDL or Triglycerides Lipid NEUTRAL = GOOD CHOICE to treat patients w/ HTN & history of hyperlipidemia - Carboxamide functional group = some 2 AGONISM Reminiscent of the salicyl group (2 directing) Provide SOME safety margin in patients with history of asthma, COPD, etc BUT still is a NON-selective -blocker (could act on 2 receptors) should ONLY use SELECTIVE 1 antagonists in patients w/ lung diseases Applying SAR Betaxolol

ArylOXYpropanolamine *note Methoxy * Naphthyl = NON-Selective Isopropyl = -directing group S Isomer = Active form of the drug

ArylOXYpropanolamine * note Methoxy * Isopropyl = -directing group Phenyl w/ PARA substituent = 1 SELECTIVE Cylcopropyl = Lipophilicity

Clinical Decisions
Aryloxypropanolamine & arylethanolamine - antagonists can be used as first line therapy for UNCOMPLICATED HTN Aryloxypropanolamine and arylethanolamine - blocker GOOD CHOICE to treat HTN in a patient with a history of myocardial infarction or tachycardia (Works on heart 1 receptors to contractility) 1 SELECTIVE compoundsArylOXYpropanolamine; para substituent with (or w/o) ortho substituent SAFER to use for treatment of HTN in patients with a history of bronchitis, COPD or Asthma -

Some beta antagonists such as Toprol XL (sustained release metoprolol) and carvedilol counteract the detrimental effects of sympathetic nervous system activation in heart failure (HF) started very low & slow and gradually If the patient does not tolerate them, or a certain target dose was NOT achieved after an extended period of slow titration = should be withdrawn NON-selective (Arylethanolamine)- antagonists triglycerides & HDL contraindicated for treatment of HTN in patients with a history of hyperlipidemia -

1 selective compounds have LESS effect on lipid levels compared to nonselective compounds Same for - antagonists with ISA (Indole ring) & -antagonists with -blocking activity (Labetalol) better choice to treat a patient with HTN and a history of hyperlipidemia Treatment of HTN a -antagonist with ISA will be a better choice to treat hypertension in a patient with a history of bradycardia Look for INDOLE ring (image above) Lipophilic -antagonists Look for Carbon chains & cyclopropyl penetrate the BBB & can contribute to CNS side effects including nightmares, insomnia psychosis & depression lipophilic compounds should be AVOIDED in patients with a history of depression, sleeping disorders and psychosis Side effects may also be detrimental to compliance HIGHLY lipophilic nature (example: Betaxololsee above) may DOA due to extensive first pass effect may affect compliance since more doses are require (due to DOA) HIGHLY polar nature for the -antagonist (example: Sotalol(above) & Timolol (below) will CNS penetration and the potential for CNS side effects contribute to enhanced excretion and a DOA

Intermediate lipophilic nature for a -antagonist ( example: Nadololsee above) Will CNS penetration but some CNS side effects may be observed Will PREVENT extensive metabolism or excretion DOA and compliance. Topical application = high lipophilic nature (example: Betaxololsee above) will contribute to distribution and the potential for side effect A BALANCED lipophilic-polar nature will distribution and potential for side effects contraindication in certain disease states (asthma, COPD, etc) -