Antihistamine, Analgesic
& Anti-inflammatory
Mary Jho-Anne T. Corpuz, Ph.D
UST-Faculty of Pharmacy
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Outline
• Introduction
• Mechanism of Action
• Uses
• Classification
• SAR
• Antihistamines
• Analgesics
• Opioid Analgesic
• Non-narcotic, Anti-inflammatory Analgesic
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ANTIHISTAMINE
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Introduction
• HISTAMINE
• β-imidazolylethylamine derivative
• Mediation of allergic and hypersensitivity
reactions and the regulation of gastric secretion
• Storage: Mast cells, Basophils,
enterochromaffin-like cells, brain.
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Histamine Receptors
Receptor Location Response
H1 Vascular SM Vasodilation
Extravascular SM Contraction
Endothelial cells Contraction
Sensory nerve endings Itch and Pain
Brain Wakefulness
H2 Gastric parietal cells HCl secretion
Cardiac muscles Atrial contraction
Uterine SM Uterine contraction
Mast cells Release of inflammatory
mediators
H3 Brain Alertness, wakefulness
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Antihistamine
• Drugs that block the action of H1, H2, and H3
receptors.
• Classification:
• Physiologic Antagonist
• Ephinephrine
• Pharmacologic Antagonist
• H1 Antagonist
• H2 Antagonist
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H1 Antagonist
• Mechanism of Action:
• Competitively inhibit the action of H1
receptors
•Uses:
• Allergic reactions
• Motion sickness, vestibular disturbances
• Nausea and Vomiting
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H1 Antagonist: Classification
1st Generation 2nd Generation
• Ethanolamine • Loratadine
(Diphenhydramine) • Cetirizine
• Ethylenediamine • Acrivastine
(Pyrilamine) • Fexofenadine
• Piperazine (Hydroxyzine) • Terfanidine
• Alkylamine • Astemizole
(Chlorpheniramine)
• Phenothiazine
(Promethazine)
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H1 Antagonist: SAR
• Ar: Aryl - Phenyl, substituted
phenyl, heteroaryl groups
• Ar’: 2nd aryl, aryl methyl group
• H1 receptor affinity
• Lipophilicity
• Para substitution of OCH3, Me, Br,
Cl - Activity
• Replacement of phenyl ring with 2-
pyridyl: Activity
• X: connecting atom of O, C, N
• (CH2) n: carbon chain
• Branching – Activity
• NRR’: Basic, terminal amine
function
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H1 Antagonist: 1st Generation
• ETHANOLAMINE
• X: CHO
• 2 or 3 carbon atom chain
• Diaryl 3o Amino Alkyl
ether
• Penetrate BBB –
Sedation
• M receptor affinity
• GI side effects
• Long duration
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H1 Antagonist: 1st Generation
• ETHYLENEDIAMINE
• X: N
• 2 carbon atom chain
• Diarylethylenediamine
(except antazoline)
• CNS depressant, GI
side effects
• Anticholinergic actions
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H1 Antagonist: 1st Generation
• PIPERAZINE
• X: CHN
• Piperazine moiety
• Sedation
• Peripheral and central
antimuscarinic activity
• Slow onset, long duration
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H1 Antagonist: 1st Generation
• ALKYLAMINE
• X: sp3 or sp2 carbon
• sp3 – pheniramines (phenyl &
2-pyridyl aryl group)
• Halogenated- more potent,
long duration
• sp2 – pyrollidino group –
Activity
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H1 Antagonist: 1st Generation
• ALKYLAMINE
• X: sp3 or sp2 carbon
• sp3 – pheniramines (phenyl &
2-pyridyl aryl group)
• Halogenated- more potent,
long duration
• sp2 – pyrollidino group –
Activity
• 2 additional carbons
• Most active H1 antagonist
• Sedation
• Anticholinergic activity
• Oral BA
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H1 Antagonist: 1st Generation
• TRICYCLIC • Phenothiazine
ANTIHISTAMINE • Antihistamine – 2 or 3
carbon, branched alkyl
chain, unsubstituted
heterocyclic ring
• Antipsychotic activity –
unbranched propyl chain
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H1 Antagonist: 1st Generation
• TRICYCLIC • Dibenzocycloheptenes/he
ANTIHISTAMINE ptanes
• Y: Vinyl or ethyl
• X: sp2 carbon
• Antihistamine, anti-5TH,
appetite-stimutating
• Sedation
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H1 Antagonist: 2nd Generation
• Selective H1 receptor affinity
• Diaryl substituted piperazines or piperidines
• Large aralkyl groups or polar groups linked to the
piperidine/piperazine rings
• Side effects: Affinity for M, adrenergic, 5TH receptors
• DOA: Long
• Non-sedating: Poor CNS penetration
• Polar nature (cetirizine)
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H1 Antagonist: 2nd Generation
• Piperidine
• Terfenadine
• Diphenylmethylpiperidine
• receptor affinity
• N-phenylbutanol substituent
• Affinity for M, adrenergic,
5TH receptors
• CNS affinity
• Fexofenadine
• Oxidative metabolite of
terfenadine
• Less cardiotoxic
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H1 Antagonist: 2nd Generation
• Piperidine
• Astemizole
• More potent than
terfenadine
• piperidino-
aminobenzimidazole moiety
• H1 receptor affinity, long
duration of action
• Loratadine
• Neutral carbamate group
has replaced the basic
tertiary amino moiety-
antihistaminic action,
reduced CNS effects,
• Phenyl ring has been
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H1 Antagonist: 2nd Generation
• Piperazine
• Cetirizine
• Polar – Reduced CNS
effects
• No cardiac effects
• Highly protein bound
• Ethoxy acetic acid
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H2 Antagonist
• Mechanism of Action:
• Inhibit the action of H2 receptors
• Uses:
• Heart burn
• Peptic ulcer disease (2nd line drug)
• Zollinger-Ellison syndrome
• GERD
• Acute stress ulcers
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H2 Antagonist: SAR
• Selectivity to H2 • Cimetidine
receptor
• 5-methyl group attached
in imidazole ring
• Higher potency
• Insertion of thioether
function in the side chain
• Competitive
antagonism
• Thiazole
• Amino alkyl furan
• Maximal antagonist
activity
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H2 Antagonist: SAR
• Selectivity to H2 • Famotidine
receptor
• 5-methyl group attached
in imidazole ring
• Higher potency
• Insertion of thioether
function in the side chain
• Competitive • Ranitidine
antagonism
• Thiazole
• Amino alkyl furan
• Maximal antagonist
activity
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H3 Antagonist
• Mechanism of Action: • SAR
• Inhibits the action H3 • Selectivity for Histamine
receptor receptors
• Uses: • 4-monosubstituted
• Tx of sleep disorders imidazole ring
(Narcolepsy) • Chains A and B
• E.g. Thioperamide
• Polar group
• Lipophilicity
• Halogenated phenyl,
cycloalkyl, heteroaryl
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ANALGESIC
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Introduction
• ANALGESICS
• Drugs that bring about insensibility to pain
without loss of consciousness.
• Classification:
• Opioid Analgesics
• Non-Narcotic, Anti-inflammatory
Analgesics
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OPIOID ANALGESIC
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Opioid Analgesic
• Drugs obtained from opium, a drug latex from incised
unripe capsule of Papaver somniferum.
• Opioid Receptors
• Location: Brain, SC
Receptor
Mu - Most active, important
Mu-1 - Location: outside spinal cord
- Central interpretation of pain
Mu-2 - Location: CNS
- Respiratory depression, spinal analgesia, physical dependence,
and euphoria
Kappa - Only modest analgesia
- Little or no respiratory depression and dependence
Delta - Poor analgesia and sedation
- little addictive potential
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Opioid Analgesic
• Essential for Receptor
Binding
• Anionic site
• Flat area for aromatic ring
• Cavity for rings
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Opioid Analgesic
• Classification:
Pure Agonist Activates mu and kappa receptors Morphine, Codeine,
Heroin, Fentanyl
Levorphanol, Methadone
Partial Agonist Blocks mu while activating kappa Pentazocine, Butorphanol
receptors
Pure Antagonist Blocks mu and kappa receptors Naltrexone, Naloxone
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Opioid Analgesic
• Classification
Examples
Phenanthrene Morphine, Codeine, Heroin,
Thebain
Pure antagonists: Naltrexone,
Naloxone
Morphinan Levorphanol
Benzomorphan Pentazocin
Phenylpiperidine Fentanyl
Open chain opioid Methadone
analgesic
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Phenanthrene: Morphine
• Prototype
• Chemistry:
• A (aromatic
ring)
• 3-OH important for
analgesic activity
• B (cyclohexane)
• C (cyclohexene)
• D (Piperidine)
• E (tetrahydrofuran)
• Use: Moderate to severe
pain
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Phenanthrene: Codeine
• Methyl ether
• Activity: 20% that of morphine
• SAR:
• Conversion of the 3-OH to 3-
OCH3
• Protects the 3-position from
glucuronide
• mu Activity
• Larger than OCH3 - Activity
• Conversion of 6-OH to a 6-OCH3
(heterocodeine) - Activity
• Use: Mild to moderate pain, cough
suppressant
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Phenanthrene: Heroin
• 3,6-diacetylester
• Activity: 2x of morphine
• SAR:
• Esterification of both the
3- and 6-OH
• Lipophilicity – easy to
cross BBB
• Potency (2-3x more
potent than morphine)
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Phenanthrene: Thebaine
• SAR:
• Adding a 6th ring across
C6 and C14 of the C ring
• Partial agonist activity:
• Replacement of N-
methyl group of
Thebaine with a
methylcyclopropyl
group (Buprenorphine)
Buprenorphine
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Morphinan
• Activity: 5x of morphine
• SAR:
• 4 rings (lacks ring E) – retain activity
• Removing ether bridge –
Analgesic activity
• 3-OH is optimal, and a 3-methoxy is
less active.
• Methylating 3-OH group
improves antitussive activity
• No other substituents may be added
to the A ring
• Ring C must be unsubstituted.
• Antagonist activity:
• N-allyl groups (Levollorphan)
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Benzomorphan
• Activity: 4x + of morphine
• SAR:
• 3 rings(Lacks rings C, E)
– retains activity
• Activity:
• Trimethyl derivatives
• N-phenyl ethyl derivative
• No addictive property
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4-phenylpiperidine
• Activity: 100x that of
morphine
• SAR:
• 2 rings (Lacks rings B, C,
E) – retain activity
• lipophilic chains on Fentanyl
active N
• Cross BBB efficiently
• Rapid onset, short duration
• Replacement of the N-
methyl group with:
• Aralkyl groups more potent
derivatives
• very bulky group produces Loperamide
inactive compounds
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Open chain Opioid Analgesic: Methadone
• SAR:
• Rings B,C,D,E opened –
retained activity
• Activity: < Morphine
• Analgesic activity:
• Both phenyl groups must be
present
• N should be 3o
• Use:
• Wean addicts off heroine or
morphine
• Advantages:
• Can be given orally
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Pure Antagonist
• Structurally related to morphine
with the exception of the group
attached to nitrogen
• SAR:
• Antagonist activity
• Replacing N-methyl group
with N-aliphatic groups:
• Cyclopropylmethylene Naltrexone
(Naltrexone)
• Allyl group (Nalorphine)
• Propyl methylene group
• Uses:
• Morphine overdose
• Heroin addicts post-rehab
• used to treat former narcotic Nalorphine
addicts
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Summary of Opioid Analgesic SAR
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ANTI-INFLAMMATORY
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Non-Steroidal Anti-inflammatory Drugs
(NSAIDS)
• Widely used for the treatment of minor pain and for the
management of edema and tissue damage resulting from
inflammatory joint disease (arthritis).
• Mechanism of Action:
• Inhibition of Cyclooxygenase
COX-1 COX-2
Gastric ulcers Reduce inflammation
Bleeding Reduce pain
Acute renal failure Reduce fever
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Non-Steroidal Anti-inflammatory Drugs
(NSAIDS): Classification
• Salicylates
• N-Anthranilic acid (fenamate)
• Aryl and Heteroarylacetic acid
• Oxicams
• Selective COX2 inhibitor
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Non-Steroidal Anti-inflammatory Drugs
(NSAIDS): Uses
• Anti-inflammation
• Analgesic
• Anti-pyretic
• Treatment of gout
• Prophylaxis of heart
disease. (Myocardial
infarction and stroke
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Non-Steroidal Anti-inflammatory Drugs
(NSAIDS): SAR
• Acidic group • Polar linking group which
• COOH, enolic, hydroxamic attaches the planar moiety to an
acid, sulfonamide, tetrazole additional lipophilic group
group. • Analgesic activity
• COX inhibition • Groups larger than methyl -
• Major binding group in plasma activity.
proteins
• Site of metabolism by
conjugation (Glucuronidation)
• Aromatic or hetroaromatic ring.
• Alkyl chain or an additional
aromatic ring
• Lipophilicity
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Salicylates
• Derivatives of 2-hydroxybenzoic acid (salicylic acid).
• COX1 selective
• Types of Salicylic acid derivative:
• Type I – formed by modifying the carboxyl group
• GI tract disturbances, stable aqueous solutions
• Type II – by substitution on the OH group
• Type IIa - Formation of an ether linkage
• Type IIb - Formation of an ester linkage
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Salicylates: SAR
• Active moiety – Salicylate • Diflunisal
anion
• COOH - GI disturbances
• Reducing the acidity of
COOH (e.g amide) – retain
analgesic, Anti-
inflammatory
• Substitution of halogens on the
aromatic ring at the 5-position
- Anti-inflammatory activity
• Phenolic OH group at m or p
- Activity
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N-Anthranilic acid (Fenamates): SAR
• N-aryl substituted
derivatives of anthranilic
acid
• NH moiety – essential for
activity
• Substitution on the
anthranilic ring - Activity
1
• Activity
6 2
• small alkyl or halogen
substituents at the 2′, 3′
and/or 6′ position of the 5 3
N-aryl moiety 4
• Effective interaction at their
inhibitory site on COX
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Aryl and Heteroarylacetic acid
• Derivatives of acetic acid
• Substituent at the 2-position is a heterocycle or related
carbo cycle.
• Classification:
• Indene
• Indoles
• Pyrroles
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Aryl and Heteroarylacetic acid: SAR
• Indene/indoles • Pyrroles
• Anti-inflammatory activity • Lacks benzylic methyl group
• Carboxyl group
• Not susceptible to oxidation
• Methoxy group on the ring (5),
• Long half life
methyl (2), dimethyl amino
group (5) in indole moiety
• Cl or F at para position of
phenyl group
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Oxicams: SAR
• 4-hydroxybenzothiazine heterocycle.
• Acidity
• 4-OH with the enolate anion being stabilized by intramolecular
hydrogen-bonding to the amide N-H group.
• COX inhibitory activity.
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Selective COX2 inhibitor
• Selectively block the COX-2 isoenzyme without affecting
COX-1 function
• Chemistry:
• Diaryl-5-membered heterocycles
• Sulfonamide group
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Selective COX2 inhibitor
Celecoxib Rofecoxib Valdecoxib
• Pyrazole ring • Furanose ring • Isoxazole ring
• 2 adjacent phenyl • 2 adjacent phenyl
substituents substituents
• CH3 group • CH3 sulfone group
• Polar sulfonamide
moiety
• Binds to hydrophilic
region on COX-2
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Aniline and p-Aminophenol Derivative
• Antipyretic and analgesic activity
• Little anti-inflammatory activity R2
• SAR:
R1
• Reducing the basicity of Amino
group - Activity
• Alkylation of N with CH3
R3
• Analgesic activity
• Irritant to mucus membrane
• Hydroxylated anilines (o, m, p) –
less toxic
• Amide derived from aromatic acid –
less active or inactive
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Aniline and p-Aminophenol Derivative
• Antipyretic and analgesic activity Paracetamol
• Little anti-inflammatory activity
• SAR:
• Reducing the basicity of Amino
group - Activity
• Alkylation of N with CH3
• Analgesic activity
• Irritant to mucus membrane
• Hydroxylated anilines (o, m, p) – Salicylanilide
less toxic
• Amide derived from aromatic acid –
less active or inactive
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• Wilson’s and Gisvold’s Textbook of Organic
Medicinal and Pharmaceutical Chemistry 11th
edition by John H. Block and John M. Beale
REFERENCES • Principles of Organic Medicinal Chemistry by Rama
Rao Nadendla
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