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H2N
H
N
H
N
N
N
COOH
Sir Henry Dale,
discovered histamine
H i s - decarboxyl as iH2N
His
Histamine
H
N
t
N
H2N
2-(1H-Imidazol-4-yl)-ethylamine
H2N
N
N
N
H
N
p
H2N
Where is located Histamine:
a)Neurons
b)Mast cells and other cells
Ruolo fisiologico dell’Istamina
L’Istamina è un autacoide sintetizzato in un ristretto n° di neuroni localizzati
prevalentementee nei nuclei tuberomamillari dell’ipotalamo posteriore.
Nei tessuti periferici è particolarmente presente nei mastociti, eosinofili, basofili,
cellule enterocromaffini.
La eccessiva liberazione di questo autacoide induce effetti di tipo
patofisiologico come:
1. contrazione della muscolatura liscia (bronchi, intestino, utero)
2. dilatazione dei piccoli vasi (arteriole, vene e capillari)
3. incremento della permeabilità dei capillari e rilascio di catecolamine dalla
midollare del surrene.
The function and evolution of mast cells
Mast cells play a key role in the inflammatory process.
When activated, a mast cell rapidly releases its
characteristic granules and various
hormonal mediators into the interstitium.
Plasma cells, also called plasma B cells,
plasmocytes, and effector B cells, are white
blood cells which produce large volumes of
antibodies. They are transported by the blood
plasma and the lymphatic system.
Like all blood cells, plasma cells ultimately
originate in the bone marrow; however, these
cells leave the bone marrow as B cells, before
terminal differentiation into plasma cells, normally
in lymph nodes.
Mast cells can be stimulated to degranulate by
direct injury (e.g. physical or chemical
[such as opioids, alcohols, and certain antibiotics
such as polymyxins]), cross-linking of
Immunoglobulin E (IgE) receptors, or by
activated complement proteins.
The role of mast cells in the development of allergy.
The substances of mast cells
The molecules thus released into the extracellular environment include:
1.
preformed mediators (from the granules):
serine proteases, such as tryptase
histamine (2-5 pg/cell)
serotonin
proteoglycans, mainly heparin (active as anticoagulant)
2.
newly formed lipid mediators (eicosanoids):
thromboxane
prostaglandin D2
leukotriene C4
platelet-activating factor PAF
3.
cytokines
Eosinophil chemotactic factor
Function of the enterochromaffin-like (ECL)
cell of the stomach.
Enterochromaffin-like cells or ECL cells are a type of neuroendocrine cells found in
the gastric glands of the gastric mucosa beneath the epithelium, in particular in the
vicinity of parietal cells.
They are also considered a type of enteroendocrine cell.
ECL cells synthesize and secrete histamine.
ECL cells are stimulted by vagal nervous through the neurotransmitter Ach.
The most important inhibitor of the ECL cell is somatostatin from oxyntic D
cells.
Gastrin is transferred from a specific type of G cell in the gastric epithelium to
the PARITAL cells by blood.
The post-ganglionic fibers of the vagus nerve that innervate the G cells of the stomach
release gastrin release peptide (GRP), which stimulates the G cells to release gastrin.
Histamine and Gastrin act synergistically as the most important stimulators of
hydrochloric acid secretion from parietal cells and stimulators of secretion of
pepsinogen from chief cells.
Enterochromaffin-like cells also produce pancreastatin and probably other
peptide hormones and growth factors.
Histamine receptors system
Histamine receptors play an important role in human disease, and drugs acting
at these receptors are clinically important.
Peripheral-selective H-1 antagonists are used in the treatment of allergies and allergic
asthma and H-2 antagonists offer treatment for gastric distress due to hyperacidity.
A third type of histamine receptor, the H-3 receptor, is a pharmacologically distinct
histamine receptor located predominantly on presynaptic nerve terminals, where it
modulates the release of histamine and other neurotransmitters.
Other etheroreceptors (M2, a2 and -opioid) have the same function to regulate
the Histamine release.
The H-3 receptor has recently gained attention for its potential role in modulating
cognitive, psychiatric, appetitive, allergic, and other physiological processes,
and there is much recent interest in finding potent and efficacious H-3 receptor
antagonists to treat these diseases.
Recently, a forth receptor H-4 was discovered and ligands were developed in
order to charactherized its function.
L-histidine
Histamine neurone activity
Nerve ending
Histamine
G protein H3/H4
Synaptical cleft
Metabolism
H3 homo/heteroreceptors:
H, Ach, 5-HT, D, NA,….
Histamine
H1
H2
Gq/G11 protein
The signal transduction pathway used by the H3/H4
receptor appears to be via Gi and Go proteins.
Gs-protein
Effector cell
IP3
DG
+ cAMP
Histamine is also a neurotransmitter in the CNS with a role in sleep-wake cycles, appetite, learning and memory.
It is produced in a subset of neurons in the tuberomammillary nucleus of the hypothalamus and its effects are
transmitted widely to other regions of the brain.
(A) Histaminergic neuron. H3 autoreceptor, endogenous histamine (HA), acts at presynaptic H3 autoreceptors to reduce HA synthesis and
release (a negative feedback loop).
(B) (B) Nonhistaminergic neuron. Blockade of the H3 heteroreceptors should modulate the release of other neurotransmitters.
aa involved in the istamine receptor interaction
Asp
Thr,
Asn
Aspetti terapeutici mediati dal sistema istaminergico
Dal prospetto fisiopatologico appare chiaro che con questo sistema bisogna contrastare
piu’ che promuovere l’attivazione dell’Istamina liberata in base a certi stimoli.
Tuttavia sono state evidenziate alcune attività terapeutiche istamino mediate:
a) attraverso il sito H1 si puo’ determinare un’attività anticonvulsivante confermata dal dato
farmacologico che gli antagonisti H1 inducono o incrementano il danno cerebrale in casi di epilessia,
b) Si puo’ incrementare l’attività del muscolo cardiaco, in alternativa al sistema adrenergico,
attraverso un’azione istamino simile mediata dal recettore H2.
Patologia relativa al sistema
istaminergico
ISTAMINE is responsible of 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.
Terapia
Dal prospetto patologico appare chiaro che bisogna contrastare piu’ che
promuovere l’attivazione dell’Istamina liberata in base a certi stimoli.
Histamine is released from preformed stores in mast cells and basophils
Molecular models of H1 antagonists, first generation
Ar 1
X Ar
2
H
N
N
H2N
R
N
R
X = N, C, C-O, C-N
and others
The first generation of H1 antagonists is poor receptor selective and pass the BBB, they
present more side effects.
Molecular models of H1 antagonists, first generation
X=N
Thonzylamine
N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyrimidin-2-ylethane-1,2-diamine
Also in association with NAPHAZOLINE, an a-agonist, in a formulation of eye drops.
Molecular models of H1 antagonists, first generation
Central activity of this H1 antagonist to treat emesis via cholinergic disactivation
X = C-O
O
CH3
N
CH3
O
N
O
N
O
(2-Benzhydryloxy-ethyl)-dimethyl-amine
Diphenydramine
N
H
N
N
Cl
8-Chloro-1,3-dimethyl-3,7-dihydro-purine-2,6-dione or
8-chloro Theofilline.
The salt is a Diphenidramine-theoclate
Molecular models of H1 antagonists, first generation
N
X=C
Cl
CH3
N
CH3
Chlorpheniramine
+/-[3-(4-Chloro-phenyl)-3-pyridin-2-yl-propyl]-dimethyl-amine
+ isomer is POLARAMIN
Molecular models of H1 antagonists, first generation
X = C-N with cyclization of the spacer and the base
Cyclizine
1-benzhydryl-4-methyl-piperazine
S
Also, cyclic structures in the
first generation of H1 antagonists
N
H3C
N
CH3
Prometazine
Dimethyl-(1-methyl-2-phenothiazin-10-yl-ethyl)-amine
Only local therapy
N
H3C
Ciproeptadine
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methyl-piperidine
Reorganization of H1 antagonists with poor side effects
From cyclizine and hydroxyzine
to CETIRIZINE
Hydroxyzine
cyclizine
Cl
N
N
O
COOH
Cetirizine
(2-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-acetic acid
Levocetirizine is a third-generation non-sedative
antihistamine, developed from the
second-generation antihistamine cetirizine.
From chlorpheniramine to the second generation of H1 antagonists, more receptor selective
and with poor side effects.
Loratadine
N
Cl
Cl
N
CH3
N
CH3
N
Chlorpheniramine
+/-[3-(4-Chloro-phenyl)-3-pyridin-2-yl-propyl]-dimethyl-amine
+ isomer is POLARAMIN
O
O
4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine-1-carboxylic acid ethyl ester
Cl
N
N
H
N
O
Cl
N
O
Des-Loratadine, CLARINEX
8-Chloro-11-piperidin-4-ylidene-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
Desloratadine (a major metabolite of loratadine) is extensively metabolized to
3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated.
HO
Cl
N
N
H
Cyclic structure and chemical function for 2° antihistamine generation
Olopatadine hydrochloride
Olopatadine is an antihistamine (as well as anticholinergic) and mast cell stabilizer, sold as a prescription eye drop (0.2%
solution, Pataday (or Patanol S in some countries), manufactured by Alcon).
It is used to treat itching associated with allergic conjunctivitis (eye allergies). Olopatadine hydrochloride 0.1% is sold as
Patanol (or Opatanol in some countries). A nasal spray formulation is sold as Patanase, which was approved by the FDA
on April 15, 2008.
It is also available as an oral tablet in Japan under the tradename Allelock,
{(11Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid
Another cyclic structure and chemical function for 2° antihistamine generation
Ketotifen
4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one
Ketotifen is a second-generation H1-antihistamine used to treat allergic conjunctivitis or the itchy red eyes caused by
allergies. In its oral form, it is used to prevent asthma attacks.
Other antisthamine design
Terfenadine
COOH
HO
HO
N
N
OH
OH
*Fexofenadine
2-(4-{1-Hydroxy-4-[4-(hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyl}-phenyl)-2-methyl-propionic acid
From haloperidol to terfenadine
*Fexofenadine is a metabolite of Terfenadine,
it has a better pharmacological profile and in
praticular less interacts with the K+ channels
O
HO
N
F
Cl
Mast cell stabilizer
Antagonists of the H1 receptor of Histamine are the more abundant drugs to prevent the action of the lignad
in pathlogical conditions.
We can aslo stabilizing the cell and thereby preventing the release of the ligand and related mediators
comprehensive of histamine.
It seems that these drugs (cromone medications) can block a calcium channels essentially for mast cell
degranulation.
Nedocromil is classified as a cromone, a derivative of benzopyran with a substituted keto group on
the pyran ring.
Nedocromil
9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid
Nedocromil acts as a mast cell stabilizer, inhibits the degranulation of mast cells, prevents release of
histamine and tryptase, so preventing the synthesis of prostaglandins and leukotrienes.
Lumen of the stomac
HCl
H+
Cl- K+
K+
H+/K+ ATPase
I principali interlocutori
della cellula secretoria
Protein kinases
+
H2 blockers
cAMP
Ca++
-
+
+
IP3 and DG
Proglumide
M3
Histamine
PGE2
Histamine M1
containing
cell
atropine
Ach
Gastrin
Plesso del nervo
vago con fibre colinergiche
enterochromaffin-like cells
Istamine and H2 receptor
Events leading to hydrochloric
acid formation by the parietal cell
Regulation of stomac secretion
Paracrine comunication by cells in the stomac
Function of the enterochromaffin-like (ECL)
cell of the stomach.
Enterochromaffin-like cells or ECL cells are a type of neuroendocrine cells found in
the gastric glands of the gastric mucosa beneath the epithelium, in particular in the
vicinity of parietal cells.
They are also considered a type of enteroendocrine cell.
ECL cells synthesize and secrete histamine.
ECL cells are stimulted by vagal nervous through the neurotransmitter Ach.
The most important inhibitor of the ECL cell is somatostatin from oxyntic D
cells.
Gastrin is transferred from a specific type of G cell in the gastric epithelium to
the ECL cells by blood.
The post-ganglionic fibers of the vagus nerve that innervate the G cells of the stomach
release GRP, which stimulates the G cells to release gastrin.
Histamine and gastrin act synergistically as the most important stimulators of
hydrochloric acid secretion from parietal cells and stimulators of secretion of
pepsinogen from chief cells.
Enterochromaffin-like cells also produce pancreastatin and probably other
peptide hormones and growth factors.
Molecular models of H2 antagonists
Imidazole ring replacement
H2N
Istamine
H
N
H
N
N
N
H2N
modification of the spacer
modification of the amino function
Design of H2 antagonists
1. modification of the amino function
NH
NH2
O
O
Amidine function
H
N
H
N
H
N
R
R
NH
S
Ureic or thioureic function
H
N
Guanidine function
Amidine and guanidine functions are considered to more basic and NO2 and CN
groups were used to modify the chemical properties, expecially in the last guanidine
2. modification of the spacer
S
In the modification of the spacer has been considered the distance between amino function and
imidazole ring and the influence of the spacer into the chemical properties of the same
imidazole ring
3. Imidazole ring or analog of this scaffold with similar
properties
N
N
H
R
Design of H2 antagonists
Burimamide was the first compound to be described
with selectivity for the H2 receptor.
Burimamide has since been shown to be a more potent
antagonist of the presynaptic H3 receptor present on
nerve terminals within the central and peripheral
nervous systems.
The development of selective H3 receptor agonists
(e.g. R- -methylhistamine, immetit) and antagonists
(e.g. thioperamide, clobenpropit, iodoproxyfan and
ciproxifan) was reported.
There is growing evidence that both the H3 and H4 receptor are potentially exciting new therapeutic targets
for neuropathological and immunological disorders, respectively, with compounds currently in Preclinical
development or Phase I and II clinical trials
Design of H2 antagonists
H H
N
N
S
N
NH2
N
N-CN
N
H
N
H
Cimetidine
istamine
N-cyanoN'-Methyl-N''-[2-(5-methyl-1H-imidazol-4-ylmethylsulfanyl)-ethyl]-guanidine
S
N
H
N
H
N
N-NO2
N
H
N
O
S
N
S
H
N
H
NO2
H
N
CH-NO2
N
H
H
N
H
N
Ranitidine
N-[2-(5-dimetilaminometil-furan-2-il-metilsulfanil)-etil]-N'-metil-2-nitro-1,1-etendiammina
S
N
N
S
H
N
H
N
H
NO2
Design of H2 antagonists
Nizatidine
N-[2-(5-dimetilaminometil-tiazol-4-il-metilsulfanil)-etil]-N'-metil-2-nitro-1,1-eten-diammina
N
NH2 N
H2N
N
S
SO2-NH2
NH2
S
Famotidine
3-[[[2-[(aminoiminometil)amino]-tiazol-4-il]-metil]-sulfanil]-N-(aminosulfonil)-propan-imideamide
NH2 N
H2N
N
S
S
H
N
NHCH3
N
CN
Tiotidine
N-cyanoN'-Methyl-N''-[[[2-(aminoiminomethyl)amino]-tiazol-4-yl]-methylsulfanylethyl]-guanidine
Design of H2 antagonists
O
N
O
O
N
H
O
Roxatidine acetate
Acetic acid [3-(3-piperidin-1-ylmethyl-phenoxy)-propylcarbamoyl]-methyl ester
Roxatidine acetate is a specific and competitive H2 receptor
antagonist.
The antisecretory effect of roxatidine acetate is mediated by
its main metabolite, roxatidine.
O
N
O
N
H
OH
Gastric acid secretion
Gastric acid is secreted by parietal cells of the stomach in response to stimuli such as the
presence of food in the stomach or intestine and the taste, smell, sight or tought of food.
Such stimuli result in the activation of hystamine, acethycoline or gastrin receptor ( the H2
M3 and CCK2) located in the basolateral membrane of the parietal cell, which initiates
signal trasduction patways that converge on the activation of H+/K+-ATPase, the final
step of acid secretion.
A proton-pump as a final step in the secretion of HCl
Plasma
CO2
HCO3-
Gastric Parietal Cell
Lumen of the
Stomach
carbonic anhydrase
CO2 +
H2CO3
H2O
H+
H+
HCO3-
K+
ATP
Cl-
Cl-
ADP + Pi
Cl-
H+,K+-ATPase
Figure 1. Production of gastric acid and its secretion
H+,K+-ATPase
Ion trasport is coupled to a cycle of phosphorylation and dephosphorylation of the enzyme.
The enzyme is composed of two subunits, the big catalitic a-subunit consists of 1000 aa and
it is responsible of the transport, and a smaller b-subunit perhaps 300 aa with a structural and
membrane-targeting function.
The a-catalytic subunit of the H+/K+ ATPase appears to have 10 membrane-spanning
segments and the loop between M5-6 contains Cys813 that may have relevant for inhibition
by drugs that are acid-activated thiol reagents.
Other Cys residues to be considered in the contest of the drug-activity are 321 in the M3-4
and 892 in the M7-8 loop.
H+
Proton pump inhibitors
Omeprazole (Losec)
Esomeprazole (Nexium)
Lansoprazole (Zoton, Lansox)
Pantoprazole (Protium)
Rabeprazole sodium (Pariet)
S
N
N
CH3
N
H
N
S
N
Chemical milestones in the development of proton-pump inhibitors
Omeprazolo
OCH3
N
O
S
N
OCH3
HN
5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl-methanesulfinyl)-1H-benzoimidazole
Lansoprazolo
CF3
O
N
O
S
N
HN
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl-methanesulfinyl]-1H-benzoimidazole
Pantoprazolo
O
O
N
O
S
N
HN
O
CHF2
5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-yl-methanesulfinyl)-1H-benzoimidazole
Rabeprazolo
O
N
O
O
S
N
HN
2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzoimidazole
Proton-pump inhibitors such as omeprazole are prodrugs that are
converted to their active form in acidic environments.
Omeprazole is a weak base, and so specifically concentrates in the acidic
secretory canaliculi of the parietal cell, where it is activated by a
proton-catalysed process to generate a sulphenamide.
The sulphenamide interacts covalently with the sulphydryl groups of
cysteine residues in the extracellular domain of the H+K+/ATPase
in particular Cys 813 thereby inhibiting its activity.
Omeprazole sulphenamide active form
H3C
OCH3
CH3
H3C
N
N
S
S
HN
O
+
N
H+
SOH
N
O
NH
H 3CO
OCH3
CH3
H3C
+
N
H+ (slow)
NH
H 3CO
OCH3
CH3
NH
H 3CO
ossidazione
H3C
OCH3
CH3 H3C
OCH3
CH3
N
+
N
S
N
H 3CO
- H2 O
NH
N
H 3CO
SH
NH
OCH3
CH3
H3C
+
N
RS
—
N
H3C
SSR
NH
+
N
RSH
ENZ-S H
H 3CO
OCH3
CH3
N
N
S
H 3CO
Sulphenamide intermediate
Altri farmaci utili per le patologie gastriche
Antiacidi: Al(OH)3, AlO(OH), Al2O3
The hydroxide reacts with excess acid in the stomach, reducing its acidity. This decrease of
acidity of the contents of the stomach may in turn help to relieve the symptoms of ulcers,
heartburn or dyspepsia.
It can also cause constipation and is therefore often used with magnesium hydroxide or
magnesium carbonate, which have counterbalancing laxative effects.
Sucralfate is a cytoprotective agent, an oral gastrointestinal medication primarily
indicated for the treatment of active duodenal ulcers.
All alcholic functions are
-C-O-SO2-O-Al(OH)2
Altri farmaci utili per le patologie gastriche
Analoghi delle PGE2 che sulle cellule non parietali, epiteliali e
della mucosa, inducono la sintesi di mucoproteine e bicarbonato
per tamponare l’acidità.
L’interazione della PGE2 con il recettore specifico delle cellule
parietali è un messaggio negativo per la sintesi di HCl.
Prostaglandin E2
Misoprostol
Fine presentazione
Models for the cation binding domain of the wild-type enzyme (left panel) and the N792Q
mutant (right panel)
Ruolo terapeutico Istamina-Recettori
Il ruolo fisiologico dell’Istamina non é del tutto chiaro (è presente nella maggior parte dei tessuti e in
conc. elevata nei polmoni, nell’epidermide e nel tratto gastrointestinale e in alcune cellule del
sangue come mastociti e basofili), mentre la eccessiva liberazione di questo autacoide induce effetti
di tipo patofisiologico come:
1. contrazione della muscolatura liscia (bronchi, intestino, utero)
2. dilatazione dei piccoli vasi (arteriole, vene e capillari)
3. incremento della permeabilità dei capillari e rilascio di catecolamine dalla midollare del surrene.
Dal prospetto fisiopatologico appare chiaro che bisogna contrastare l ’eccessiva attività dell’Istamina
liberata in base a certi stimoli o impedire l’attvità di questa sostanza mediata dai rispettivi siti
recettoriali.
Tuttavia sono state evidenziate alcune attività terapeutiche istamino mediate, per esempio
attraverso il sito H1 si puo’ determinare un’attività anticonvulsivante confermata dal dato
farmacologico che gli antagonisti H1 inducono o incrementano il danno cerebrale in casi diepilessia,
oppure incrementare l’attività del muscolo cardiaco, in alternativa al sistema adrenergico
attraverso un’azione istamino simile mediata dal recettore H2.
Hydroxyzine, ATARAX
2-[2-[4-(p-chlorobenzhydryl)-1-piperazinyl]ethoxy]ethanol dihydrochloride.
Prostaglandins
The development of agents active at prostaglandin (PG) E2 receptors has
been an area of interest to the pharmaceutical industry for the past three
decades, with both agonists and antagonists anticipated to have therapeutic
utility in treating diverse conditions including asthma, inflammation,
pain, ulcers, cancer, and osteoporosis.
PGE2 has been shown to be the preferred prostanoid ligand for four of these
receptor subtypes, the EP1, EP2, EP3, and EP4 (EP2 and EP4 receptors coupled to
an increase in intracellular cAMP are smooth muscle relaxants.
EP2 and/or EP4 antagonists play an important role in diminishing allergic and IgE-mediated
asthmatic responses since EP2 and EP4 subtypes regulate activation and differentiation of mouse B
lymphocytes to IgE-secreting cells.
Other prostanoids interact with:
PGD-2 for the DP receptor,
PGF-2a for the FR receptor,
PGI-2 for the IP receptor, and
TXA-2 for the TP receptor.
Prostaglandins and therapy
Protective of gastric mucosa,
O
COOCH3
CH3
HO
OH
MISOPROSTOL, a PGE2 analogues
(11a, 13E) 11,16-diidrossi-16-metil-9-oxo-prost-13-en-1-oico acido metil estere
O
HO
CH3
OH
HO
RIOPROSTIL
(11a, 13E) 1,11,16-triidrossi-16-metil-prost-13-en-9-one
Cl
H3C
HO
OH
CH3
COOH
NOCLOPROST
(9R, 11R, 15R) 9-cloro-11,15diidrossi-16,16-dimetil-prosta-5Z,13E-dienoico acido
Vasodilatant in perifery,
O
HO
COOH
OH
CAVERJECT
(11a, 13E) 11,15-diidrossi-9-oxo-prost-13-en-1-oico acido
Stimulant of the uterus muscle
O
HO
HO
COOH
OH
PGE2
(11R, 15R) 9-oxo-11,15-diidrossi-prosta-5Z,13E-dienoico acido
HO
COOH
OH
PGF2a
(9R,11R, 15R) 9,11,15-triidrossi-prosta-5Z,13E-dienoico acido
Modificazioni molecolari dell’His/Istamina
CF3
H
N
N
H2N
2-(1H-Imidazol-4-yl)-2-(3-trifluoromethyl-phenyl)-ethylamine, agonista selettivo H1
More modifications
N
HN
S
H
N
H
N
H
N
N
NH
Impromidine
N-[3-(1H-Imidazol-4-yl)-propyl]-N'-[2-(5-methyl-1H-imidazol-4-ylmethylsulfanyl)-ethyl]-guanidine, agonista selettivo H2
Modificazioni molecolari dell’His/Istamina
H
N
N
H2N
2-(1H-Imidazol-4-yl)-1-methyl-ethylamine, agonista H3
Gli agonisti del recettore H3 possono essere proposti
nell’infiammazione neurogenica (vie aeree e vescica),
migrain e nei disordini del sonno.
H
N
H
N
N
H
N
N
S
4-(1H-Imidazol-4-yl)-piperidine-1-carbothioic acid cyclohexylamide, antagonista H3
N
H
N
O
O