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ADRENERGICADRENERGIC ANTAGONISTSANTAGONISTS
•Mechanism of action: irreversible(covalent bond) inhibition of α1 and α2 receptors (Nonselective).•Therapeutic uses: Pheochromocytoma•Side effects: Postural hypotension, nasal stuffiness, inhibit ejaculation and reflex tachycardia.
O
CH3
NCl
phenoxybenzamine
•Mechanism of action: competitive blocking for α1 and α2 receptors.•Therapeutic uses: short term management of pheochromocytoma, to treat impotence.•Side effects: Postural hypotension, reflex tachycardia., nasal congestion,
N
N NH
OH
CH3
phentolamine
•Mechanism of action: selective α1 antagonist.•Therapeutic uses: Hypertension.
N
N
N
N
O
O
CH3
OCH3
NH2
O
Prazocin (Minipress)
•Mechanism of action: selective α1 antagonist.•Therapeutic uses: hypertension.
N
N
N
N
O
CH3
OCH3
NH2
OO
O
Doxazocin (Cadura)
•Mechanism of action: selective α1A antagonist.•Therapeutic uses: BPH
S
O
O
NH2
O
CH3
CH3NH
H
O
OCH3
Tamsulosin(FloMax)
1. 1. -Adrenoceptors-Adrenoceptors
NotesNotes•G-Protein-coupled receptorsG-Protein-coupled receptors•Activate generation of cyclic AMPActivate generation of cyclic AMP
33-Adrenoceptor-Adrenoceptor •Predominant receptor in fat cellsPredominant receptor in fat cells•Activation results in fat metabolismActivation results in fat metabolism
22-Adrenoceptor -Adrenoceptor •Predominant receptor in bronchial smooth muscle Predominant receptor in bronchial smooth muscle •Activation results in smooth muscle relaxationActivation results in smooth muscle relaxation
11-Adrenoceptor -Adrenoceptor •Predominant receptor in heart musclePredominant receptor in heart muscle•Activation results in cardiac muscle contractionActivation results in cardiac muscle contraction•Antagonists of this receptor are potential cardiovascular drugsAntagonists of this receptor are potential cardiovascular drugs
2. Natural messengers 2. Natural messengers
Noradrenaline - neurotransmitterNoradrenaline - neurotransmitter
HO
HO
NH2R
OHH
Adrenaline - hormoneAdrenaline - hormone
HO
HO
NHMeR
OHH
NotesNotes•Activate all adrenergic receptorsActivate all adrenergic receptors•No selectivityNo selectivity
3. Lead compound 3. Lead compound
•Isoprenaline is aIsoprenaline is a-agonist rather than antagonist-agonist rather than antagonist•Shows selectivity for Shows selectivity for -adrenoceptors-adrenoceptors•NN-Isopropyl group is responsible for selectivity-Isopropyl group is responsible for selectivity
HO
HO
HN
H OH
IsoprenalineIsoprenaline
Isopropyl groupIsopropyl group
4. Converting an agonist to a partial agonist 4. Converting an agonist to a partial agonist
NotesNotes•Phenol groups are not required for antagonist activityPhenol groups are not required for antagonist activity•Add extra binding groups to convert an agonist to an antagonistAdd extra binding groups to convert an agonist to an antagonist•Hydrophobic groups form extra van der Waals interactionsHydrophobic groups form extra van der Waals interactions•Structure binds but produces a different induced fitStructure binds but produces a different induced fit•Act as partial agonists Act as partial agonists
- weakly activate receptors- weakly activate receptors- block natural messenger- block natural messenger
HO
HO
HN
H OH
IsoprenalineIsoprenaline(agonist)(agonist)
Cl
Cl
HN
H OH
DichloroisoprenalineDichloroisoprenaline(partial agonist)(partial agonist)
HN
H OH
PronethalolPronethalol(partial agonist)(partial agonist)
5. Converting a partial agonist to an antagonist 5. Converting a partial agonist to an antagonist
Notes on propranololNotes on propranolol•Spacer introduced - chain extension strategySpacer introduced - chain extension strategy•Substituent is positioned at a different part of the ring Substituent is positioned at a different part of the ring •Ether group acts as a hydrogen bond acceptor (extension strategy)Ether group acts as a hydrogen bond acceptor (extension strategy)•10-20 times greater antagonist activity10-20 times greater antagonist activity•Used clinically as a racemateUsed clinically as a racemate•SS-Enantiomer is the active enantiomer-Enantiomer is the active enantiomer•Aryloxypropanolamine structureAryloxypropanolamine structure•Activates Activates 11 and and 22 adrenoceptors adrenoceptors
HN
H OH
PronethalolPronethalol(partial agonist)(partial agonist)
HN
X
OHH
2
•Introduce spacer Introduce spacer (chain extension)(chain extension)•Vary substituent positionVary substituent position
O NHOHH1
PropranololPropranolol(antagonist)(antagonist)
EtherEther
SpacerSpacer
O NHOHH1
PropranololPropranolol(antagonist)(antagonist)
NN-Alkyl-Alkylgroupgroup
7. SAR on aryloxypropanolamines 7. SAR on aryloxypropanolamines
NotesNotes•Ether acts as a hydrogen bond acceptorEther acts as a hydrogen bond acceptor•Ether can be replaced with an alternative HBA (O or NH)Ether can be replaced with an alternative HBA (O or NH)•Alcohol is essential as a hydrogen bonding groupAlcohol is essential as a hydrogen bonding group•Amine is ionised and forms an ionic bond with the binding siteAmine is ionised and forms an ionic bond with the binding site•Amine must be secondaryAmine must be secondary•Naphthalene is replacable with heteroaromatic ringsNaphthalene is replacable with heteroaromatic rings•Branched Branched NN-alkyl group fits a hydrophobic pocket-alkyl group fits a hydrophobic pocket•Extension of Extension of NN-alkyl group with -alkyl group with NN-arylethyl group is beneficial-arylethyl group is beneficial
OH
O NH
EtherEther
AlcoholAlcohol
NaphthaleneNaphthalene
AmineAmine
OH
O NH
OH
O NH
SubstitutionSubstitutionlowers activitylowers activity
Aryloxy groupAryloxy group
OH
O NH
PropanolaminePropanolamine groupgroup
Aryloxy groupAryloxy group
OH
O NH
8. Variation of the naphthalene ring 8. Variation of the naphthalene ring
PropranololPropranolol
OH
O NH
O NH
NH
OHHO N
H
N S
NN
O OHH
PindololPindolol TimololTimolol
NotesNotes
•Propranolol acts against both Propranolol acts against both 11 and and 22-adrenoceptors-adrenoceptors
•Cannot be used with asthmatic patientsCannot be used with asthmatic patients
•Antagonism of Antagonism of 22-adrenoceptors constricts airways-adrenoceptors constricts airways
•Second generation Second generation -blockers are designed to be -blockers are designed to be 11 -selective -selective
9. Second generation 9. Second generation -blockers -blockers
9. Second generation 9. Second generation -blockers -blockers
O NH
NHCOCH3
OHH
NotesNotes•Selective cardiac Selective cardiac 11-antagonist-antagonist•More polar More polar •Less CNS side effectsLess CNS side effects•First cardioselective First cardioselective 11-blocker used for the treatment of angina and -blocker used for the treatment of angina and
hypertensionhypertension•Withdrawn due to serious side effects in some patientsWithdrawn due to serious side effects in some patients
PractololPractolol
Practolol - binding interactionsPractolol - binding interactions•Amido group must be Amido group must be parapara for for 11-selectivity-selectivity•Extra hydrogen bonding interaction takes placeExtra hydrogen bonding interaction takes place•Not possible with Not possible with 22-adrenoceptor-adrenoceptor
9. Second generation 9. Second generation -blockers -blockers
para substitutionExtra H-bonding interaction
meta substitution
HN CH3
O
XH
OH
O NH2
NH
H3C
O
XH
OH
O NH2
Other agentsOther agents
9. Second generation 9. Second generation -blockers -blockers
OH
O NH
NHCOnPr
O
OH
O NH
CH2CONH2
OH
O NH
CH2CH2OMe
OH
O NH
CH2CH2OCH2
AcebutololAcebutolol AtenololAtenolol MetoprololMetoprolol BetaxololBetaxolol
NotesNotes•Includes an Includes an NN-arylalkyl group -arylalkyl group •Additional hydrogen bonding interactions are possibleAdditional hydrogen bonding interactions are possible•Extension strategyExtension strategy
10. Third generation 10. Third generation -blockers -blockers
EpanololEpanolol
NC
O
OH
NH
HN
O
PrimidololPrimidolol
H3C
O
OH
NH
N
HNO
O
CH3
XamoterolXamoterol OH
O
OH
NH
HN
O
N
O
Extra H-bonding interactionsExtra H-bonding interactions
EpanololEpanolol
NC
O
OH
NH
HN
O
PrimidololPrimidolol
H3C
O
OH
NH
N
HNO
O
CH3
XamoterolXamoterol OH
O
OH
NH
HN
O
N
O
•Mechanism of action: non selective β Blocker•Therapeutic uses: effect on heart, eye and lungs. Used for migraine, hyperthyroroidism•Side effects: bronchoconstricion, sexual\d impairment, increases sodium retension, masking hypoglycemia, and reduces glycogenlysis
O
NH
OH
CH3CH3
Propranolol(Inderal)
•Mechanism of action: non selective β Blocker, more potent than propranolol. It has long duration of action•Therapeutic uses:
OH
OH
O
NH
OH
CH3CH3
CH3
Nadolol (Corgard)
•Mechanism of action: non selective β Blocker, more potent than propranolol.•Therapeutic uses: Txt of chronic open-angle glaucoma. N
O
N
N
S
O
NHCH3
CH3
OH
CH3
Timolol
•Mechanism of action: Non-selective β blocker. It has intrinsic agonist activity (B3).•Used to trt pts of HTN and HF.
O
NH
OH
CH3CH3
NH
Pindolol
•Mechanism of action: selective β 1 blocker. It has intrinsic agonist activity. Less disturbance on the fat and CH metabolism.•Therapeutic uses: hypertension . It can be used for HT in diabetics. It cannot be used for arrythemia.•Side effects: coldness of extremities (less common than non selective).
O
NH
CH3
CH3
NH
CH3
OH
CH3
O
O
Acebutolol
•Mechanism of action: selective β1 blocker.•Cheap and selective O
NH
CH3
OH
CH3
NH2O
Atenolol (Hypoten)
•Mechanism of action: selective β1 blocker, very short time of action so only for parental use•Structure-based explanation of Therapeutic uses: hypertension
O
NH
CH3
O
OH
CH3
O
CH3
Esmolol
•Mechanism of action: selective β1 blocker
O
NH
CH3
OH
CH3
O
CH3
Metoprolol(lopresor)
•Mechanism of action: β+ α1 blocker.•Therapeutic uses: elderly and black people (it has peripheral vasodilatation). It is also alternative of methyldopa in perganant women. It is used for emergency as \well because of its efficacy.•Side effects: orthostatic hypotension.
NH
OH
CH3
NH2
O
OH
Labetalol
•Mechanism of action: β+ α1 blocker. It reduces lipid peroxidation so good for heart failure.(Cardioprotective)
NH ONH O
OH
O
CH3
Carvedilol(Dilatrend)
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