Transcript Document

Tust Techasith
11-30-04
Medicinal Chemistry
Dr. John Buynak
“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
NH2
5
4
3
1
H
N
N
2
Histamine
Sir Henry Dale,
discovered histamine
“histamine mediates the allergic
symptoms by binding to some receptor
of histamine on the cell”
NH2
5
4
3
1
H
N
N
2
Histamine
C2H5
H3 C
N
O
C
H2
C
H2
929F: Toxic
C2H5
CH3
H3 C
2-isopropy l-5-methy l phenoxy ethy l diethy lamine (929F)
Me
C N
H2
C C N Et
H2 H2
Me
Antergan
RP2339: The first
compound that was
used to treat human
clinically.
H1, H2, H3, H4: All GPCR’s
H1: brain, smooth muscle from airways,
gastrointestinal (GI) tract, genitourinary system, the
cardiovascular system, adrenal medulla, and endothelial
cells, and lymphocytes.
Target of Antihistamines
“compete against the receptors’ natural substrate,
histamine, in binding to the receptors “
R
Ar
X
A r'
C
H2
n
N
R'
General H1 Receptor Antagonist
CH3
C
H
O
C C N
H2 H2
HCl
CH3
Diphenhy dramine Hy drochloride
• 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.
CH3
C
H
O
C C N
H2 H2
HCl
CH3
Side Effects: fatigue, dizziness, and
sedation.
Due to: the peripheral anticholinergic
effects and the “interactions with a
number of neurotransmitter systems
in the CNS”
Diphenhy dramine Hy drochloride
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.
“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”
OH
OH
N
CH2CH2CH2
C
H
CH3
CH3
COOH
Fexof enadine
Eliminated anticholinergic and
antiadrenergic effects via bulky groups.
Researches also show that
fexofenadine cannot cross the bloodbrain barrier (note the polar COOH and
OH).
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”.
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.
“constitutive receptor activity”
Dynamic equilibrium between the active form
(R*) and the non-active form (R).
Dynamic Equilibrium
Agonist Binding
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.