PHCY258 Introduction to Drug Action
Autonomic Pharmacology
L23 Medicinal Chemistry of Adrenergic Drugs
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Lecture 23: Dr Joel Tyndall
Medicinal Chemistry of Adrenergics
β2 - Adrenoreceptor - drug target β1 - Adrenoreceptor - drug target
Agonist Antagonist
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Medicinal Chemistry of Adrenergics
Learning Objectives - Lecture
• Recognise the importance of receptor selectivity
• Understand the SAR of β (selective) agonists
• Understand the SAR of β (selective) antagonists (β blockers)
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Medicinal Chemistry of Adrenergics
References
Patrick, G.L. (2009)
An Introduction to Medicinal Chemistry 4th Ed.
Oxford University Press;
Ch. 23, pp 609-626
Lecture 09 - Drug Targets - Receptors
Lecture 16 - SAR (Optimising target interactions)
Lecture 18 - Lead Optimisation (Optimising Access)
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Adrenaline & Adrenergic receptors
Neurotransmitter/Hormone & their receptors
H OH H OH H
HO NH2 HO N
HO HO
Noradrenaline Adrenaline
(Norepinephrine) (Epinephrine)
• Adrenergic receptors (adrenoreceptors) are central and peripheral
and tissue selective.
• Two main types: α & β
GPCRs
• Subtypes α1 & α2, β1 & β2
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• other types: α1A, α1B,...etc, β3
Distribution & Effects
Organ /Tissue Receptor Effect of activation Physiological effect
Heart muscle β1 Muscle contraction ↑ heart rate / force
Bronchial smooth α1 Smooth muscle contract. Closes airways
muscle β2 Smooth muscle relax Dilates / opens airways
Arteriole smooth α Smooth muscle contract Constricts arterioles ↑ pressure
muscle β2 Smooth muscle relax Dilates arterioles
Veins α Smooth muscle contract Constricts veins ↑ pressure
β2 Smooth muscle relax Dilates veins ↓ pressure
Liver α1 & β 2 Activates enzymes Breakdown glycogen →
glucose
GI tract smooth α1, α2 & β2 Relaxation Shut down digestion
muscle
Kidney β2 ↑ renin secretion ↑ blood pressure (Angiotensin)
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Uses of Adrenergics
Receptor Effect of activation Physiological effect
α1 Agonists Hypotension
Antagonists Antihypertensives
Benign Prostatic Hyperplasia
α2 Agonists Antihypertensives
Glaucoma
Analgesia
Sedatives
β1 Antagonists Antihypertensives*
Antiarrythmics
β2 Agonists Bronchodilators*
Glaucoma
β3 Agonists Weight loss (future)
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Uses of Adrenergics
Quick Reference
α1 - Vasoconstriction
(Narrowing of blood vessels - muscular contraction)
α2 - Acts presynaptically to inhibit transmitter release
β1 - ↑ cardiac force and rate (cardiac receptor)
β2 - Bronchodilation, vasodilation
(Dilates - airways)
(widening of blood vessels - smooth muscle relaxation) 9
Adrenergic Binding site
Catecholamines
H OH H OH H
HO NH2 HO N
HO HO
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Adrenergic SAR
SAR
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Selectivity for receptor α/β subtypes
Optimisation
H OH H OH H2 H OH H2
HO NH3 HO N HO N
HO HO HO
Noradrenaline Adrenaline Isoprenaline
• Adrenaline - same potency for α-adrenoreceptors and β-adrenoreceptors
• Noradrenaline - greater potency for α−adrenoreceptors
• N-alkyl group contributes to selectivity
• Isoprenaline - β-adrenoreceptor selective
Larger N-alkyl group increase β receptor selectivity
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How does this relate to receptor?
Selectivity for receptor α/β subtypes
H OH H OH H2 H OH
HO NH3 HO N HO NH3
HO HO HO
Noradrenaline Adrenaline α-Methylnoradrenaline
Phenolic groups:
• more important for β than α (hydrogen bonding) - COMT metabolism
α-methyl substitution:
• addition of α-methyl increases α2-selectivity
• slows metabolism by MAO (monoamine oxidase) How?
Extension (strategy - optimise interactions)
• Isoprenaline - β-selectivity
• larger alkyl group with polar substituent
↑ activity (x800) H OH H2
Why? HO N 13
HO OH
Adrenergic Agonists
H OH H2
HO N
Adrenaline
HO
• Used emergency situations - cardiac arrest or anaphylactic shock (bee
sting, nut hypersensitivity) - intramuscular injection - Epipen
• Fast acting - short duration of action
• rapid metabolism by intestinal and liver COMT and MAO,
3-glucuronidation / sulfation
• Low oral bioavailability
• Hits all adrenergic receptors! Side effects
• Need selectivity
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Adrenergic Agonists
General Adrenergic Agonists
• Ephidrine - natural product (herbal remedy) - exists as a racemate
• activates α- and β-adrenoreceptors
• used extensively as a non-prescription bronchodilator
• also cardiac stimulant
• Pseudoephidrine - found naturally - (diastereomer of ephidrine)
• Nasal decongestant
• Amphetamines
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Adrenergic Agonists
Selective Adrenergic Agonists
α1, α2, β1, ..., β3 agonists...generally limited scope
• α-selective adrenoceptor agonists
•constrict blood vessels, raise blood pressure and can cause
cardiovascular problems but some useful ones
Cl
H H
N N
N
Cl
Clonidine - α2 selective - hypertension (stimulates α2 receptors in the brain)
decreasing cardiac output
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β2 Selective Agonists
Treatment of Asthma
• β2 receptor activation results in smooth muscle relaxation
• broncho-dilation
• Adrenaline - short acting and non-selective (cardiovascular issues)
• Isoprenaline - β selective but activated β1 in the heart (no subtype selectivity)
• α (ethyl) substitution (isoetharine) was selective for β2 but short acting
H OH H2 H OH H2 H OH H2
HO N HO N HO N
HO HO HO
COMT
Adrenaline Isoprenaline
H OH H2
O N
(inactive) 19
HO
β2 Selective Agonists
Treatment of Asthma
• To avoid COMT inactivation, varied groups at meta position
• Sulfonamide - long acting β2 selective agonist (not used clinically)
• Hydroxymethylene - salbutamol (albuterol U.S.)
O OH H OH H2
S N N
HO
H OH H2
N
HO
Optimising access to a target: HO
More resistant to enzymatic degradation 20
β2 Selective Agonists
H OH H2
HO N
Salbutamol HO
• equipotent with isoprenaline BUT 2000x less active on the heart
• 4 hrs duration
• racemic mixture R-68 x more active: S-enantiomer causes side effects
• pure R-enantiomer levalbuterol marketed H OH H2
N
HO
HO
SAR - Meta substituent:
• must be able to make hydrogen bonds
• EWG have poor activity (COOH)
• bulky groups - bad - prevent H-bonding
• CH2OH or CH2CH2OH but no more 21
β2 Selective Agonists
H OH H2
HO N
Developing other “drugs” HO
N-alkyl substituents
• Extension strategy (polar binding pocket)
• Salmefamol - 1.5 x more active; longer duration of action - 6 hrs
• Needed longer lasting agents - increase lipophilicity
• Salmeterol -2 x as potent as salbutamol - duration of action of 12 hours
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Salmefarol Salmeterol
β2 Agonist SAR
Summary I
H OH H2
HO N
• Important binding groups of catecholamine
HO
• Bulky N-alkyl group leads to β-selectivity
• Extension of N-alkyl group access H-bonding interaction ↑ β-receptor
affinity
• Replace Phenol OH prevents COMT metabolism
• Increase lipophilic character ↑ duration of action
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Adrenergic Receptor Antagonists
General non-selective blockers
• Carvedilol - antihypertensive, cardiac failure
• Labetalol - antihypertensive
O
OH
H
HN O N
O
O OH
H
N
H2 N
HO
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α Blockers
α-selective blockers
• Limited to α1 selective blockers:- Hypertension and limiting urine output
• Prazosin - first - short acting treatment - hypertension
• Doxazosin & Terazosin - long lasting (daily dose)
• Block α1 receptors in smooth muscle in blood vessels
→ relaxation ↓ blood pressure
NH2
O
Prazosin N
O N N O
N
H OH H2
HO N O
HO NH2 NH2
O O
N N
O N N O O N N O
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N O N
Doxazosin O
Terazosin O
β Adrenoceptor Antagonists
β blockers in cardiovascular medicine
Lead Development H OH H2
HO N
Isoprenaline (first lead) as it was selective for HO
Isoprenaline
β receptors (agonist)
H OH H2
Cl N
• Replace hydroxyls (not so important for antagonism)
Cl
• Dichloroisoprenaline - partial agonist - Dichloroisoprenaline
(not complete activation) H OH H2
N
blocks binding of natural chemical messengers
• Replace with aromatic group - slightly different Pronethalol
binding (induced fit)
Pronethalol - still partial agonist - 1st β blocker used clinically 26
β Blockers
β blockers in cardiovascular medicine
Chain Extension strategy between aromatic ring H OH H2
N
and ethanolamine
Original target
Propranolol - pure antagonist - 10-20 x greater activity than pronethalol
angina - benchmark drug - Nobel prize 1988
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H OH H2
HO N
β Blockers HO
SAR - Aryloxypropanolamines
O N O N
H OH H2 O H OH H2
N N
N N S
H 28
Pindolol Timolol (both non-sel.)
β Blockers
1st Generation (non-selective) β blockers
H OH H2
HO N
HO
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Foyes 6th p411
Adrenoreceptor Selectivity
β2 - Adrenoreceptor - Agonist β1 - Adrenoreceptor - Antagonist
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β Blockers
1st Generation (non-selective) β blockers
• Originally intended for angina now antihypertensives (lower blood press.)
• Effects:
• act at heart to ↓ output
• act at kidneys to ↓ renin release (Renin-Angiotensin system)
• Renin helps form angiotensin I → angiotensin II
• vasoconstrictor
•Side effects: remember ACE inhibitors!
• bronchoconstriction in asthmatics BAD!
Need a selective drug!
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β Blockers
2nd Generation (β1 selective) β blockers
O N
OH
H Practolol (less potent) but selective - much safer for asthmatics
HN
Serious side effects (in a few) caused its withdrawal
O
Further med. chem. investigations conducted
• Amide must be in the para position (not ortho or meta) for selectivity
Implies extra hydrogen bonding interaction in β1 receptors but not β2
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β Blockers
2nd Generation (β1 selective) β blockers
Replace para acetamido group.....
H OH H2
HO N
HO
Short half-life: why?
Metoprolol Bioprolol
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cardioselective β1-blockers Foyes 6th p411
β Blockers
3rd Generation β blockers
N-alkyl extension led to additional H-bonding interactions
Xameterol - highly selective partial agonist
• provides cardiac stimulation when patient is at rest
• acts as a blocker during exercise
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β Blocker Development & SAR
Summary II β blockers
HO
• Replace catechol ring with naphthalene: agonist to partial agonist HO
• Linking group variation led to β selective antagonists
• SAR of aryloxypropanolamines showed important features for activity
*O N
H
OH
* *
#
• 1st generation non-selective - asthma issues (propranolol “contraindicated”)
• 2nd generation show β1 selectivity (hydrogen bonding group at para position)
• 3rd generation extra hydrogen bonding interaction (N-alkyl extension) 35
Uses of Adrenergics
Quick Reference
β1 - ↑ cardiac force and rate (cardiac receptor)
β blockers - Antihypertensives*
β2 - Bronchodilation, vasodilation
(Dilates - airways)
(widening of blood vessels - smooth muscle relaxation)
Bronchodilators*
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