ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR (Structure Activity Relationship )
Structure activity relationship (SAR) Adrenergic drugs · PPT file · Web...
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Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist and Neurone blockers
DR. ISHOLA I.O. PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGYCMUL
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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
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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
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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
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SAR
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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)
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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
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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
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Adrenergic receptor agonist/antagonist
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Adrenergic agonist/antagonist
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Adrenergic System
ALPHA BLOCKERS:Non-selective Phenoxybenzamine, Phentolamine
Alpha -1 selective Prazosin, Terazosin, Tamsulosin
Alpha-2 selective Yohimbine
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Adrenergic System
BETA BLOCKERS:
Non selective : Propranolol, Nadolol, Timolol With Partial agonist : PindololBeta 1 selective : Atenolol, MetoprololBeta and alpha 1 blocker : Labetolol, Carvedilol
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Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible
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NH3
COOH
Gq
Phospho-lipase C
(+)
PIP2
IP3 Diacylglycerol
Increase Ca2+ Activate ProteinKinase C
Response
Receptor agonists activate signal transduction pathways
a1 adrenergic receptor
HO
HO CH
OH
CH2 NH2
Norepinephrine
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Receptor antagonists block agonist binding to the receptor
NH3
COOH
Gq
Phospho-lipase C
Antagonist
HO
HO CH
OH
CH2 NH2
Norepinephrine
What effect would an antagonist alone have on receptor activation?
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Clinical pharmacology of a-adrenergic receptor antagonists
Drug ReceptorRoute ofadmin. Clinical uses
Side effects of a1 receptor antagonists:
Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
Phenoxybenzamine a1, a2 Oral Pheochromocytoma, hypertensive crisisPhentolamine a1, a2 Parenteral Pheochromocytoma, hypertensive crisis,
male impotencePrazosin a1 Oral Hypertension, benign prostatic
hypertrophyTerazosin a1 Oral Hypertension, benign prostatic
hypertrophyDoxazosin a1 Oral Hypertension, benign prostatic
hypertrophy
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Non-selective adrenergic receptor antagonistsb-Haloalkylamines
N CH2 CH2 XR
RR= aromatic, alkylX= Cl-, Br-, etc.
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b-Haloalkylamines
NO
CH3
Cl
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
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b-Haloalkylamines: Mechanism of receptor inactivation
receptor alkylatedreceptor
N
Cl
R RN
R R Cl-
Aziridinium ion
NR R Cl-
Nu
NR R
Nu
Non-selective adrenergic receptor antagonists
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Imidazolines
Phentolamine (Regitine)
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
Non-selective adrenergic receptor antagonists
N
NH
N
HO
H3C
CH2
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Reversible vs. Irreversible receptor blockade
-10 -8 -6 -40
50
100
Log [Norepinephrine]
a1 A
dren
ergi
cre
cept
or a
ctiv
atio
n
-10 -8 -6 -40
50
100
Log [Norepinephrine]
a1 A
dren
ergi
cre
cept
or a
ctiv
atio
n1 M Phent
+ Phentolamine + Phenoxybenzamine
10 M Phent
1 M Phenox
10 M Phenox
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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
N
NH3CO
H3CONH2
N
N R
O
O
OO
O
Prazosin: R =
Terazosin: R =
Doxazosin: R =
Quinazoline ring
Piperazine ring
Acylmoiety
(Minipres)
(Hytrin)
(Cardura)
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Other a adrenergic receptor antagonistsErgot alkaloids
N
N
O
R'O
R
O NH
O NCH3
NH
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
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a2-adrenergic receptor antagonists
Yohimbine (Yocon)
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
NH
N
H
H
H3CO2C
H
OH
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b-adrenergic receptor antagonists
Ar
O NH R
OH
Ar = aromatic ring structure
R = bulky alkyl group (isopropyl or tert-butyl)
AryloxypropanolaminesNote: non-carbon atomin side chain
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b-adrenergic receptor antagonists
Non-selective Lipophilic Local anesthetic
properties Blockade is activity-
dependentPropranolol(Inderal)
O NH
OH
CHCH3
CH3
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b-adrenergic receptor antagonistsPharmacological 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
Propranolol(Inderal)
Therapeutic uses for b-adrenergic receptor antagonists:Hypertension, angina, cardiac arrhythmias, migraine, stage fright,
thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
O NH
OH
CHCH3
CH3
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Non-selective b-adrenergic receptor antagonists
Thiadiazole nucleus with morpholine ring
Administered: Oral, Ophthalmic Uses: Hypertension, angina,
migraine, glaucoma
O NH
OH
C
CH3
CH3
CH3
N S
NNO
Timolol (Timoptic, Blocadren)
O NH
OH
CHCH3
CH3HO
HONadolol (Corgard)
Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in
urine Administered: Oral Uses: Hypertension, angina,
migraine
How will b-blockers affectpupil size?
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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
O NH
OH
CHCH3
CH3
NH
What would a pindolol dose-response curve look like?
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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
Carteolol (Cartrol, Ocupress)
NH
O
O NHOH
CCH3
CH3
CH3
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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
R
OHO N
HCH
CH3
CH3
Metoprolol (Lopressor, Toprol)R= CH2
Bisoprolol (Zebeta)R= O
O CH3
CH2CH2
OCH
CH3
CH3
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Selective b1-adrenergic receptor antagonists
Atenolol (Tenormin)
“Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina
O NH
OH
CHCH3
CH3
NH2
O
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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
O NH
OH
CHCH3
CH3
OCH3
O
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Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
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Action Potential
Na+
Effect of chronic b-receptor blockade
Presynaptic neuron
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
NE
MAO
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Action Potential
Na+
Effect of chronic b-receptor blockade: Receptor up-regulation
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
NE
MAO
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Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
Contraindications: Asthma, COPD, congestive heart failure (Type IV)
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Mixed adrenergic receptor antagonists
Labetalol (Normodyne, Trandate)
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
HN
OH
CH3HO
CONH2
11'
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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
OCH3
ONH
O
OH
NH
b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
Administered: Oral Uses: Hypertension, congestive
heart failure (Types II and III)
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Action Potential
Na+
Pharmacologic manipulation of the adrenergic system
Presynaptic neuron
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
b
NE
MAO
12
3
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Inhibition of norepinephrine synthesis
HO CH2 CH NH2
HO
HO CH
OH
CH2 NH
CH3
HO
HO CH
OH
CH2 NH2
COOH
HO CH2 CH NH2
COOH
HO
HO
HO CH2 CH2 NH2
TYROSINE
DOPA
DOPAMINE
NOREPINEPHRINE
EPINEPHRINE
tyrosine hydroxylase
aromatic L-amino acid decarboxylase
dopamine b-hydroxylase
phenylethanolamine-N-methyltransferase
MetyrosineX
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Action Potential
Na+
Drugs that reduce storage or release of NE
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
NE
NE
b
NE
MAO
ReserpineGuanethidine
GuanethidineGuanethidine,Bretylium
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Catecholamine depleters
Slow onset of action Sustained effect (weeks) Used in the treatment of
hypertension May precipitate depression
NH
N
H3CO2C
H3CO
H
H
H
OC
OCH3
OOCH3
OCH3
OCH3Reserpine (Serpasil)
Indole alkaloid obtained from the root of Rauwolfia serpentina
Block vesicular monoamine transporters
Deplete vesicular pool of NE
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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)
N
HN
CNH2
NH
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Action Potential
Na+
Drugs that reduce storage or release of NE
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
NE
NE
b
NE
MAO
Guanethidine
GuanethidineGuanethidine,
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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)Br
CH N
CH3
CH3
CH2CH3 CH3O3S
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OBRIGADO