Med Chem lectures on H1 blockers

1. Antihistaminic

2. Histamine -Pharmacology
• Histamine is an Autacoid , which are biological
chemicals which act like local hormones, have a
brief duration, and act near their site of
synthesis.
• Histamines has various function in body such as:
– Mediator of inflamation and local immune
responses
– regulating physiological function in the gut and
– acting as a neurotransmitter.
• .

3. • During inflammation Histamine is produced by
basophils and by mast cells, found in nearby
connective tissues, which increases the permeability
of the capillaries to white blood cells and some
proteins, to allow them to engage pathogens in the
infected tissues
• In the gut it is produced by parietal cells and then
promotes gastric acid secretion and thus aids in
digestion. Here it acts like a local hormone
• As a neurotranmitter, it effects sleeping and waking,
food intake, thermal regulation, emotions and
aggressive behavior, locomotion, memory, and
learning

4. Histamine - Chemistry
• Histamine is a Nitrogenous base. It is composed of an
imidazole ring and ethylamine side chain. In Plasma pH
of 7.4 is exists in exclusively monocationic form
(96.6%). At lower pH higher levels of dication form
exist.
• In solution form, 80% contain H in Nτ tautamer and
20% in Nπ tautamer
• But crystal form consist primarily of Nτ form

5. At plasma pH
96.6% is
monocationic
Lower pH favors
dicationic form
80% has
H in Nτ
20% has
H in Nπ
Nτ tautamer Nπ tautamer
Note that sp2 N is
more basic than
sp3 N

6. Histamine Biosynthesis
Note- There some drugs that can block Histidine Decarboxylase such as
Floromethylhistine which in theory can act as direct acting antihistamine
but clinically were found to be not useful.

7. Storage and release
• Stored in mast cells in Complex with Heparin
(anticoagulant)
• Stored in basophiles in Complex with Chondrotin
• Histamine as stored in mast cells are found
almost everywhere : skin and the mucosal cells of
the bronchi, intestine, urinary tract, and tissues
adjacent to the circulation and within neurons of
CNS
• It is released in response to a wide variety of
immune (antigen and antibody) and nonimmune
(bacterial products, xenobiotics, physical effects,
and cholinergic effects) stimuli

8. Histamine receptors
Location and function
H1, H2, H3, H4; they all are GPCR’s
• H1 Location : CNS neurons, the smooth muscle of
respiratory, GIT, uterine tissues, epithelial and
endothelial cells, immune cells
Function: vasodilation, vascular permeability,
hypotension, flushing, pain, headache, tachycardia,
nasal congestion, bronco-constriction, stimulation of
cough receptors, allergic immune response
• Therapeutic usage: H1 antihistamine are anti-
allergic, and anti-emetic drugs,
• H1 receptor is 40% similar to muscarinic receptors
(thus some H1 antagonist shows unwanted
antimuscaric side effect)

9. • H1 receptors belong to the superfamily of G protein
coupled receptors (GPCRs), and are encoded for by
chromosome 3
• these receptors exhibit spontaneous activation of their
intracellular messengers, requiring no binding by an agonist
at surface level
• It exists as a balance between activated (characterized by
the production of intracellular second messengers) and
inactive (no such intracellular signaling) state.
• If the ligand stabilizes the active receptor conformation,
making it the predominant form, then the drug is referred
to as an agonist, while if the inactive conformation is
stabilized the drug is said to be a inverse agonist. In this
way, histamine is an agonist, while the antihistamines are
presently considered to be inverse agonists instead of
antagonists as previously believed

11. • H2 function - gastric acid secretion, vascular
permeability, hypotension, flushing, headache,
tachycardia, broncho-dilation and respiratory mucus
production
• Therapeutic use – H2 antihistamines are Anti-ulcer
drugs
• H3 Location : CNS
• Function: adrenaline release and autoreceptor of
Histamine in CNS
• Therapeutic use – potential application against obesity
• H4 function : differentiation of hematopoietic cells
• Therapeutic use – none yet

12. Differentiation
• It is a process by which a less specialized cell
becomes a more specialized cell type
• When cells divide into daughter cells, they are
the same exact cells. This is cell division/growth
• But differentiation means when cells “divide”,
different cell types are formed.
• At conception we all were just a single cell but
differentiation causes us to have diverse
specialized cells that make up different organs

13. Undifferentiated cell, called stem cells
differentiates into diverse functioning cells
RBC
WBC
Bone
Insulin

14. Actions of Histamine by receptors

15. Adverse effects

16. Fig: Effects of H1 antihistamines at histamine, adrenergic, cholinergic, and serotonin-binding receptors. Many second
generation antihistamines do not enter the brain and, therefore, show minimal CNS effects.

17. H1 antihistamines
• Their main application is as anti-allergic, anti-emetic and
• The first generation of H1 antihistamines has sedative effect
due to effect on H1 receptor in brain. Structurally this effect is
linked to their high lipophilicity induced BBB penetration and
also they are poor substrate for brain’s endothelial P-
glycoprotein efflux pumps, thus can’t exist the brain once they
enter.
• They also antagonize cholinergic receptors which causes dry
mouth, dizziness, fatigue and are alpha adrenergic blockers
which can cause cardiotoxicity by prolonging the QT interval
• The second generation are more selective for H and don’t
penetrate brain and thus has no sedation or cardiotoxicity
• MOA: They bind and stabilize the inactive form of H1 receptors
onto which Histamine is not capable of binding.

18. Therapeutic Uses:H1 blockers
1. dermatosis
2. allergic rhinitis
3. motion sickness & emesis
4. Parkinson’s disease
5. EPS
6. Insomnia

19. ECG of heart and prolonged QT interval
•The QT interval denotes
time period taken by heart to
empty it’s blood.
•Prolonged QT interval
Suggests problem in cardiac
muscle’s repolarization
mechanism after each
contraction.
•It is a dangerous side effect
that can cause ‘Ventricular
Fibrillation' which will lead
to sudden death unless a
defibrillator is used to reset
heart’s normal rhythm

20. Classification
First Generation
1) Propylamines - Chlorpheniramine, Phenindamine
2) Ethanolamines - Diphenhydramine, Clemastine
3) Ethylenediamines - Pyrilamine, Tripelennamine
4) Phenothiazines - Promethazine, Trimeprazine
5) Piperazines - Cyclizine, Meclizine
6) Heptanes – Azatadine, Cyproheptadine
7) Phthalazinone – Azelastine
Second Generation (Peripherally Selective)
1) Piperazine- Cetirizine/Levocetirizine
2) Piperidines - Fexofenadine, Loratadine /Desloratadine
Note: Antihistamines have a lot of structural diversity

21. Structures
Propylamines EthylenediaminesEthanolamines
Piperazines
Heptanes
Phenothiazines

22. SAR of H1 antihistamines (1st gen only)
General framework of Anticholinergics
C X (CH2) N substituent
R1
R3
R2
n
Note the similarity in H1 antihistamines and Anticholinergics
(this explains the origin of Anticholinergic side effect of H1
antihistamines)
General framework of AntiHistamine (Ethanolamine based)

23. 1. It needs a tertiary amine which is mostly di-
methyl substituted or part of cyclic ring
2. The methylene (-CH2-)groups can be about 2 or 3
3. The oxygen can be removed or replaced with C
4. The terminal carbon must have two aromatic
groups and R group is mostly H but can be CH3
too

24. 5) Alkyl Substitution in these aromatic rings
influence selectivity
• Increasing alkyl substituions at C4 increases
anticholinergic activity and decreases
antihistaminic activity
• Increasing alkyl substituions at C2 decreases
anticholinergic activity and modestly increases
antihistaminic activity
6) Presence of halogen at C4 position enhances
potency
7) Replacement of one of the aromatic rings with
2-pyridyl group increases histaminic selectivity
8) For max potency, the terminal carbon must have
R configuration. R/S configuration at amine is
less important

25. C O CH2 CH2
R1
N
1
2
3
4
5
6
2C2C2C 2C CH
CH3
CH3
C
CH3
CH3
CH3
C2H5
CH3
Methyl Ethyl
i-propyl t-butyl
Alkyl position Anticholinergic Antihistaminic
At C2 Increases Decreases
At C4 Decreases Increases
Effect of increasing Alkyl group at C2 or C4

26. Halogen at C4
increases potency
2-pyridyl ring increases
histaminic selectivity

27. Importance of stereomeric consideration
Clemastine has two chiral centres, terminal carbon and amine
ED50 reflect potency. Entry 1st and 3rd are most potent. Both
contain R configuration at terminal carbon. Conversely Entry
2nd and 4th with S configuration at terminal carbon are the
least potent
Configurati
on (C,N)
ED50
mg/kg
R,R 0.04
S,S 5.0
R,S 0.28
S,R 11.0

29. Chlorpheniramine
• It is a propylamine based 1st generation H1
antihistaminic
• It is chlorinated pheniramine which improves potency
10 times and changing toxicity
• It’s Dextro isomer has S configuration and called
DexChlorpheniramine is more potent
• It also acts as serotonin-norepinephrine reuptake
inhibitor or SNRI
• It is combined with opiods for cough medicine because
it can potentiate action of opiods
• It causes drowsiness by penetrating into brain and
acting on H1 receptor
• Uses
– Allergic rhinitis, in cough medicines
• MOA (from above)

30. Draw dextro isomer of Chlorpheniramine
in fisher projection

31. Zimelidine is an anti-depressent. It is a derivative of brompheniramine
Note how a simple addition of double bond completely altered
pharmacology of drug. But was this structural alteration randomly
discovery or fully Intended?
Brompheniramine
H1 antihistaminic/Antiallergic
Zimelidine
Selective Serotonin
reuptake inhibitor/
Antidepressent

32. Clemastine
• It is a ethanolamine based 1st generation H1
antihistaminic
• This class has a longer duration of action (10-12
hrs)
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– Allergic rhinitis, urticaria (itchy skin rash), anti-emetic
• MOA (from above)

33. Pyrilamine
• It is a ethylenediamine based 1st generation H1
antihistaminic
• They are among the weakest antihistamines
• It is combined with opiods for cough medicine
because it can potentiate action of opiods
• It causes drowsiness by penetrating into brain and
acting on H1 receptor
• Uses
– Allergic rhinitis, incest bites (topically)
• MOA (from above)

35. Promethazine
• It is a phenothiazine based 1st generation H1
antihistaminic
• It’s sedative action is strong to be used clincally
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– Allergic rhinitis, motion sickness, anti-emetic,
sedative
• MOA (from above)

36. Meclizine
• It is a Piperazine based 1st generation H1
antihistaminic
• It has weak antihistaminic activity
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– anti-emetic and motion sickness
• MOA (from above)

37. Cyproheptadine
• It is a Heptane based 1st generation H1
antihistaminic
• It possesses both antihistamine and anti-
serotonin activity and is used as an anti-itch
agent
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– Allergic rhinitis, allergic conjunctivitis, allergic skin
urticaria, hypersensitivity reactions
• MOA (from above)

38. 2nd generation H1 antihistamines
• They don’t act on H1 receptor in brain because their
lower lipophilicity doesn’t allow them to penetrate
the BBB
• They have low lipophilicity due to addition of
hydrophilic groups OH, and COOH in the 1st gen
molecules. (other hydrophilic groups can be
NH2,NO2,SO4,PO4)
• They have low affinity for off-targets such as
muscarinic, adrenergic, and serotonergic receptors
• Advantage – negligible sedation, no cardiotoxicity
• Limitation – high selectivity for H1 prevents their use
as anti-emetic, during motion sickness, potentiate
cough medicines
• MOA – same as above

40. Fexofenadine
• It is a piperadine based 2nd gen H1 antihistaminic
• It produces no clinically significant
Anticholinergic or α1-adrenergic blocking or
sedative effect at therapeutic doses and is safe
even in higher doses
• It needs only single dosing daily
• Uses
– Allergic rhinitis, chronic urticaria
• MOA (from above)

41. Cetirizine/Levocetirizine
• It is a Piperazine based 2nd gen H1 antihistaminic
• It produces no clinically significant Anticholinergic
or α1-adrenergic blocking or sedative effect at
therapeutic doses
• It needs only single dosing daily
• It’s R-enantiomer, called Levocetrizine, has 30-
fold higher affinity than the S-enantiomer
• Uses
– Allergic rhinitis, relief from urticaria, water
eyes caused by hay fever
• MOA (from above)

42. Wilson and gisvold’s textbook of organic medicinal and pharmaceutical chemistry

43. Prospect of β3 agonist as anti-obesity
drug
• Around 1980’s, Agonists of β3 adrenergic
receptor was found to cause lipolysis, fat
oxidation, energy expenditure and insulin
action
• This lead to hopeful research into anti-obesity
and type 2 diabetics
• In vivo effect in rodents was also confirmed
• However as of 2014 no good drug has ever
cleared human testing
Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans. Curr
Pharm Des. 2001 Sep;7(14):1433-49

44. • The failure has been attributed to
– Compounds that succeeded in rodent, such as CL-
316,243, did not perform in same way in human
due to pharmacological differences
– the lack of selectivity of previous compounds for
the beta(3)-AR over beta(1)-/beta(2)-ARs, and
– Newer compounds have unsatisfactory oral
bioavailability and pharmacokinetic properties
– Newer compounds did not lose weight when
used chronically

45. History of anti-obesity drugs
• The last anti-obesity drug was approved in
1999 was olristat
• Recently 3 new drugs have been approved
• Contrave
• Qnexa/Qysmia
• Belviq
• Future possibility : GLP-1 agonist