Tust Techasith

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Antihistamines
Tust Techasith 11-30-04 Medicinal Chemistry Dr.
John Buynak
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Anaphylaxis
markedly improved susceptibility
to a specific protein after a suitable incubation
period -- Charles Richet,
1902
Current definition sudden, severe, potentially
fatal, systemic allergic reaction that can
involve various areas of the body (such as the
skin, respiratory tract, gastrointestinal tract,
and cardiovascular system). Common cause Food,
Insect stings, Medicines, Latex
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Histamine
Sir Henry Dale, discovered histamine
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Receptor Theory
histamine mediates the allergic symptoms by
binding to some receptor of histamine on the
cell
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Mechanism of Allergy
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First Antihistamines
929F Toxic
RP2339 The first compound that was used to treat
human clinically.
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Histamine Receptors 1, 2, 3....
H1, H2, H3, H4 All GPCRs
H1 brain, smooth muscle from airways,
gastrointestinal (GI) tract, genitourinary
system, the cardiovascular system, adrenal
medulla, and endothelial cells, and lymphocytes.
Target of Antihistamines
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First Geneneration (Classical) Antihistamines
compete against the receptors natural
substrate, histamine, in binding to the
receptors
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Benadryl

• Relieve allergic rhinitis (seasonal allergy)
  symptoms including sneezing, runny nose, itching,
  and watery eyes
• Relieve itching and swelling associated with
  uncomplicated allergic skin reactions.
• Control coughs due to colds or allergy.

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Benadryl
Side Effects fatigue, dizziness, and
sedation. Due to the peripheral
anticholinergic effects and the interactions
with a number of neurotransmitter systems in the
CNS
Structure fits relatively well to serve as an
anticholinergic agent (specifically at the
muscarinic receptor) and has the ability to
penetrate the blood brain barrier due to their
relative lipophilicity.
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Second Geneneration (Non-Sedative) Antihistamines
the primary objective of antihistamine research
over the past 10-15 years has centered on
developing new drugs with higher selectivity for
H1 receptors and lacking undesirable CNS actions
Goal designing antihistamines with reduced
ability to penetrate the CNS and decreased
affinity for central histamine receptors
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Allegra
Eliminated anticholinergic and antiadrenergic
effects via bulky groups. Researches also show
that fexofenadine cannot cross the blood-brain
barrier (note the polar COOH and OH).
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What about the other receptors?
H2 mediate the histamine induced gastric acid
secretion. Antihistaminic agents that target H2
receptor such as cemetidine and tagamet are used
to treat some gastrointestinal diseases such as
peptic ulcers.
H3 neural autoreceptor (presynaptic) serving
to modulate histamine synthesis and release in
the CNS one step up in the chain of histamine
action
H4 found primarily in intestinal tissue, spleen,
thymus, and immune active cells (such as T cells,
neutrophils, and eosinophils), which suggests an
important role for H4 receptors in the regulation
of immune function.
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Recent Findings...Inverse Agonism?
Classically speaking, histamine-mediated actions
are said to be activated by histamine binding to
the receptor and triggering some other actions
such as the inflammatory response. Thus, the
early antagonistic activity on histamine
receptors is attributed to the antagonist binding
and competitively blocks the natural substrate
from binding.
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Recent Findings...Inverse Agonism?
constitutive receptor activity
NEW THEORY
Dynamic equilibrium between the active form (R)
and the non-active form (R).
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Inverse Agonism
Dynamic Equilibrium
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Inverse Agonism
Agonist Binding
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Inverse Agonism
Inverse Agonist Binding
Because of their important implications for the
proper understanding of drug action, the concepts
of constitutive GPCR activity and inverse agonism
are currently receiving considerable attention in
the field of drug discovery.