Transcript Document

Il sistema oppioide
Un sistema neuronale
Different Types of NT
1.
Amine
a.
2.
Acetylcholine (Ach)
Monoamines
a.
b.
Catecholamines
i.
Dopamine
ii.
Norepinephrine
Indoleamines
i.
3.
4.
Serotonin
Amino Acids
a.
Glutamate
b.
Aspartate
c.
GABA
d.
Glycine
Peptides
 Many different peptides are found in
the brain and many have a
prominent role as NT.
Opioid peptides
 Found in the CNS and PNS
 Met-/Leu-enkephalin, ß-endorphin,
dynorphin and others are
neurotrasmitters
A group of other peptide as neurotrasmitters are:
Substance P and neurokinins A and B,
cholecystokinin (CCK), neurotensin,
neuropeptide Y (NPY), bradykinin, etc.
Both are found in the spinal cord and the brain
and sensory neurons associated with pain.
Pituitary hormones:


oxytocin and vasopressin
Peptides may act as NT at certain synapses and
also act as hormones.
Brain areas of opioid system
This positron emission tomography (PET) scan of opioid
system in the human brain shows the highest
concentrations in the thalamus (red) which is
involved in pain,
intermediate concentrations in the
cerebral cortex (green),
basal ganglia (yellow and orange)
which plays an important role in movement and
emotions.
Low levels in the visual cortex (violet).
Peptides are the ligands of opioid receptor system
Opioid peptides
Nociceptin H-Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln-OH
Precursor protein of opioid receptor
endogenous ligands
Opioid receptor system
To date, four GPCR opioid receptors have been cloned, the MOP ( m, mu
for
morphine), the KOP (k, kappa for ketocyclazocine), the DOP (d delta for
deferens because it was first identified in mouse vas deferens), and the
NOP-R [initially called LC132, ORL-1, or nociceptin/orphanin FQ receptor].
Opioid receptor structure
The pain pathways, ascending and descending pathways
Another rappresentation of the pain pathway and interventions that can
modulate activity at each point.
Inhibitory and
excitatory mediators
in the ascending
pathways
The side of action of the major class of analgesics
Il neurone oppioide, utilizzando il proprio neurotrasmettitore (peptide oppioide),
riduce l’ attività a livello periferico e centrale della percezione del dolore.
Molecular mechanism of opioid system
The euphoric effects of opioids, the non-therapeutic activity of opioids
Mechanism of opioid ligands in pain transmission
During pain trasmission, excitatory amino acids (such as L-Glu/L-Asp) and neuropeptides
(such as CGRP, calcitonin-gene ralated peptide) and substance P (neurokinin-1) are released
from primary afferent nerve terminals to act on their postsynaptic receptors,( NMDA, CGRP-R
and NK1-R).
This cause the production of second messangers, such as prostaglandins and NO in the
projection neurons which feed back to the primary afferent neuron to enhance presynaptic
neurotrasmitter release.
Opiates decrease pain trasmission presynaptically by reducing
neurotrasmitters release and postsynaptically by hyperpolarizing the
projection neuron.
Adaptation in presynaptic excitatory aa or neuropeptide release in their receptor activity or
intracellular messanger activity, may reduce opiate action and contribute to the development
of opiate tolerance.
Other therapeutic potentials are: antitussive and gastrointestinal disorders,
opioi derivatives are also substances of abuse (euphoric state, fear reducing,
fantasy enhancing property are then obtained).
Implication of sensory neurons, C-fibers (non myelinated) and A-d
fibers (myelinated), in the propagation of pain
The nociceptor terminals, TRP receptors
Schematic structure of TRPV-1 monomer, the subunits assemble as tetramers around a central
aqueous pore, producing nonselective cation channels
Capsaicin
Solid arrows indicate transient receptor potential vanilloid subfamily, member 1 (TRPV1)-sensitizing stimuli.
The red arrows indicate negative regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), calcium and calmodulin.
Receptors and cognate ligands known to mediate the sensitization of TRPV1 are shown on the left.
These largely sensitize TRPV1 through protein-kinase activation, although increased arachidonic acid metabolite
production and PIP2 hydrolysis are also important.
Coloured circles represent amino-acid residues that have been identified to be important in particular functions: orange,
vanilloid binding (Y511, S512, L547, T550); blue, protein kinase phosphorylation sites (S116, T370, S502, T704, S800);
and green, low-pH activation (E600, E646). The red line indicates the carboxy-terminal domain of TRPV1, which has
been shown to interact with both PIP2 and calmodulin.
Activation of thermoTRPs by naturally occurring compounds
Questa slide per dimostrare che ci sono diversi TRP receptors
Schematic depiction of the predicted membrane topology of the thermoTRPs and their activation by natural ligands.
These channels are thought to have six transmembrane domains with a proposed pore region between segment 5 and 6.
The amino and carboxy termini are cytoplasmic. Channels with ankyrin repeats in their amino termini are indicated.
In addition to their thermal sensitivity, thermo transient-receptor-potential (thermoTRP) channels are activated by natural
compounds. TRP vanilloid subfamily, member 1 (TRPV1) is activated by capsaicin, which is responsible for the piquancy
of hot-chili peppers; TRP melastatin subfamily, member 8 (TRPM8) by menthol, the active ingredient in green mint;
TRP ankyrin subfamily, member 1 (TRPA1) by pungent compounds such as cinnamaldehyde, isothiocyanates and allicin,
active ingredients in cinnamon, horseradish and garlic, accordingly; TRPV1 and TRPV3 by camphor, isolated from the
wood of the camphor laurel tree (Cinnamomum camphora); and TRPV4 by bisandrographolide, present in the Chinese
herbal plant Andrographis paniculata
Chemical structures of selected TRPV1 ligands
Capsaicin, the pungent ingredient in hot-chilli peppers; resiniferatoxin, an ultrapotent capsaicin analogue isolated
from the cactus-like plant Euphorbia resinifera Berg; N-arachidonoyl-dopamine, an endogenous lipid mediator in brain
nuclei; and the first generation transient receptor potential vanilloid subfamily, member 1 (TRPV1)
antagonist, capsazepine.
The molecular pharmacology of TRPV1
•
•
•
•
TRPV1, similar to other TRP channels, is a putative six-transmembrane-spanning
protein with a pore region localized between transmembrane segments 5 and 6.
Consistent with a role in nociception, TRPV1 is a non-selective cation channel
with a preference for calcium that is directly activated by capsaicin and noxious
temperatures ﾑ with an activation threshold in vitro of approximately 43｡C
TRPV1 RNA and/or protein expression has been described in various discrete
cells, but it is most prevalent in sensory neurons. As reviewed elsewhere, there
is mounting evidence that TRPV1 expression is regulated in sensory neurons at
the transcriptional and post-transcriptional levels.
The growing list of agents that can activate and/or sensitize TRPV1 include: mild acidification;
bradykinin (an endogenous inflammatory peptide that causes hyperalgesia); nerve-growth
factor; anandamide (arachidonoylethanolamide); arachidonic acid metabolites such as Narachidonoyl-dopamine (NADA) and N-oleoyldopamine; lipoxygenase products (12hydroperoxyeicosatetraenoic acid (12-HPETE) and 15-HPETE); leukotriene B4;
prostaglandins; adenosine and ATP; prokineticins; polyamines (such as spermine, spermidine
and putrescine); and venoms from jellyfish and spiders.
The vanilloid receptor TRPV1
•
capsaicin-containing creams
have been in clinical use for
decades to relieve painful
conditions such as diabetic
neuropathy.
•
Capsaicin is unique among naturally
occurring irritant compounds in that
the initial neuronal excitation that it
evokes is followed by a durable
refractory state during which the
previously excited neurons are
unresponsive to a broad range of
seemingly unrelated stimuli.
This effect, traditionally referred to as
desensitization, has a clear therapeutic
potential.
•
•
The peripheral termini of
capsaicin-sensitive neurons are
sites of release for various proinflammatory neuropeptides such
as substance P (SP) and
calcitonin gene-related peptide
(CGRP) that, in turn, initiate the
biochemical cascade collectively
known as neurogenic
inflammation.
•
TRPV1 antagonists are of great
interest in that they represent a new
strategy in pain relief.
Zucapsaicin
Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain.
It is the cis-isomer of capsaicin.
(Z)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
Oppium and its application
Oppium and its extracts have been used for therapeutic purposes.
Morphine isolated from oppium is one of the most widly used analgesics today.
Therapeutic potential and demand of new analgesics have resulted in developmentof a
number of new opioid analgesics.
In 1926, morphine was isolated from the opium poppy by Adam Sertürner.
This was a breakthrough in phytochemistry, because it was the first alkaloid
ever to be isolated.
Only morfine and codeine, as natural compounds, have a therapeutic utility
Oripavine
Oripavine possesses an analgesic potency comparable to morphine,
however, it is not clinically useful due to severe toxicity and
low therapeutic index.
In both mice and rats, toxic doses caused tonic-clonic seizures
followed by death, similar to thebaine.
Morphine undergoes biotransformation in the liver; the phenolic hydroxyl-groups
(position 3) and alcoholic hydroxyls (position 6) conjugate with glucuronic acid.
Codeine is metabolised by Cytochrome P-450 (D6).
Chemical nomenclature of morphinan derivatives
(-)morphine
HO
CH 3
N
H
O
oripavine
N
CH3
OH
N-metil-7,8-dideidro-3,6-diidrossi-4,5-epossi-morfinano
HO
O
OCH3
6,7,8,14-tetradeidro-4,5-epossi-6-metossi-17-metil-morfinan-3-olo
H
N
H
*
*
*
Morfinano
Fenantrene
SAR of morphine
CH3
N
HO
H
HO
O
H2N
OH
*
O
Tyr1
Peptide oppioide
*S
Analogia strutturale tra la morfina e la parte N-terminale del ligando peptidico.
L’importanza delle funzioni chimiche nelle due molecole segue questo ordine:
1.Funzione basica
2.Funzione aromatica
3.Sostituzione aromatica di tipo fenolico
4.Chiralità del morfinano
N
CH 3
H
HO
O
OH
Morphinan
derivatives as
opioid ligands
CH 3
N
Opioid agonists
H
with a morphinan structure
Codeine
3HCO
N
O
HO
CH3
OH
N
H
H
N
HO
Idromorphone
N
CH3
Ossimorphone
O
O
O
O
O
O
Idrocodone
O
N
O
CH3
OH
Eroina
1.
2.
O
H 3CO
O
OH
HO
CH3
H
O
CH3
3.
Ossidazione della posizine 6
Idrogenazione della
posizione 6,7
Ossidazione della posizione
14
H 3CO
O
Ossicodone
O
N
Other morphinan derivatives
CH 3
H
O
HO
Levorphamol
N
CH3
OH
N
CH3
H
H
H 3CO
3-idrossi-N-metil-morfinano
3-metossi-N-metil-morfinano
H 3CO
Destromethorfano
Levorphanol is more active than morphine and it is a selective
reuptake inhibitor of Norepinephrine
Codeine, destromethorfan
and racemethorfan are typically
antitussive drugs.
Oripavin derivatives
N
HO
O
CH3
OCH3
Oripavine and Tebaine (3-OCH3-Oripavine)
N
R
N
H
H
OH
R1
HO
O
R
OH
R1
OCH3
HO
N
6,14-endoetheno-tetrahydrooripavinici
O
OCH3
6,14-endoethano-tetrahydrooripavinici
H
OH
HO
O
OCH3
Buprenorphine
17-ciclopropilmetil-a-(1,1-dimetil-etil)-a-metil-4,5-epossi-3-idrossi-6-metossi-6,14-etano-morfinan-7-il-metanolo
Opioid antagonists
3,14-idrossi-17-allil-4,5-epossi-morfinan-6-one
3,14-idrossi-17-ciclopropil-metil-4,5-epossi-morfinan-6-one
N
OH
HO
Butorphanol, agonist
N
Different alchylation of nitrogen can determine partial agonist activity in morfinan structure
HO
Xorphanol, agonist
Butorphanol exhibits partial agonist and antagonist activity at the μ opioid receptor and agonist activity at the κ opioid receptor
A derivative of morfinan structure with selected therapeutic application
Nalfurafine
Nalfurafine (INN and USAN; also known as AC-820, TRK-820) is a κ-opioid receptor agonist
being developed as a treatment for uremic pruritus in people undergoing hemodialysis.
N
Morphan/Azocin derivatives
H
a profile of m/k-ligands
O
HO
6,7-Benzomorphan or benzo-azocin derivatives
H
N
Morphan or 2-aza-biciclo-[3,3,1]-nonan
Azocine
H
N
N
6,7-benzomorphan
CH 3
Benzo[d]-azocine
H
OH
Morphan/Azocin derivatives,
a profile of m/k ligands
N
HO
Pemtazocine
2-(3-methyl-but-2-enyl)-5,9-dimethyl-2’-hydrossi-6,7-benzomorphan
N
HO
Pemtazocine
6,11-Dimethyl-3-(3-methyl-but-2-enyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol
4-Aril piperidines,
a profile of m-agonist
N
CH 3
H
HO
O
OH
N
N
O
O
Meperidine
1-Methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester
N
O
Fentanil
N-(1-Phenethyl-piperidin-4-yl)-N-phenyl-propionamide
Fentanil derivatives
R3 or isoster of Ph
R2
N
R1
N
O
R
O
O
N
S
O
N
N
O
O
Ramifentanil
1-(2-Methoxycarbonyl-ethyl)-4-(phenyl-propionyl-amino)-piperidine-4-carboxylic acid methyl ester
N
O
O
Sufentanil
N-[4-Methoxymethyl-1-(2-thiophen-2-yl-ethyl)-piperidin-4-yl]-N-phenyl-propionamide
Another potent opioid derivative for animal use
Carfentanil was first synthesized in 1974 by a team of chemists at Janssen Pharmaceutica which included Paul Janssen.
It has a quantitative potency approximately 10,000 times that of morphine and 100 times that of fentanyl, with activity in
humans starting at about 1 microgram. It is marketed under the trade name Wildnil as a general anaesthetic agent for
large animals.
Carfentanil is intended for animal use only as its extreme potency makes it inappropriate for use in humans.
Currently sufentanil, approximately 10-20 times less potent (500 to 1000 times the efficacy of morphine per weight) than
carfentanil, is the maximum strength fentanyl analog for use in humans.
Aril-alkylamino derivatives,
a week m-agonists
N
CH 3
H
HO
N
O
Methadone
± 6-Dimethylamino-4,4-diphenyl-heptan-3-one
O
OH
Other aril-alkylamino derivatives
N
O
O
Propoxyphene
Propionic acid 1-benzyl-3-dimethylamino-2-methyl-1-phenyl-propyl ester
Racemic ERYTRO
Dextromoramide
(3R)-3-methyl-4-morpholin-4-yl-2,2-diphenyl-1-pyrrolidin-1-yl-butan-1-one
Opioid for gastrointestinal disorders
Cl
Cl
O
N
N
OH
O
F
OH
Haloperidol
N
Methadone
O
N
Loperamide
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N,N-dimethyl-2,2-diphenyl-butyramide
Loperamide reduces the motility of cyrcular and longitudinal free gastrointestinal musculature
Racecadotril
(RS)-benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally
acting enkephalinase inhibitor.
Unlike other medications used to treat diarrhea, which reduce intestinal motility,
racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into
the intestine.
Thiorphan is the active metabolite of racecadotril.
The drug design of thiorphan will be well illustrated during the next protease inhibitors
Analgesic drugs with partially opioid mechanism
Drugs for descending pathway
CH3
N
H
N
H 3CO
H 3CO
HO
Tramadolo
O
OH
CODEINE
(+/-) 2-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexanol
Tramadolo is a racemic mixture of both R and S stereoisomers
Tramadol posseses weak opioid agonist properties and inhibits norepinephrine (NE) and serotonin
(5-HT) reuptake.
Analgesic drugs with partially opioid mechanism
Drugs for descending pathway
N
CH 3
H
HO
Tapentadol
O
OH
MORPHINE
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride
Tapentadol is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake
inhibitor
Pain control out of opioid system
Adrenergic a2 receptor is involved in
modulation of glutamate and SP
Cl
H
N
N
N S
H
N
N
Tizanidine
a2 Receptor agonists
like Clonidine are
special analgesics
Tizanidine (trade names Zanaflex, Sirdalud) is a drug that is used as a muscle relaxant. It is a centrally
acting α2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by
medical problems such as multiple sclerosis, ALS, spastic diplegia, back pain, or certain other injuries to
the spine or central nervous system.
Pain control out of opioid system
Sodium channel is involved in
modulation of glutamate and SP
Local anesthetics are
used to control pain
Other biological systems involved in pain controll
1.
Cholinergic agonists/antagonist (Epibatidine and R(+) Iosciamine)
2.
Tachykinin antagonists (Substanc P, Neurokinin-A and Neurokinin-B are peptides)
3.
Bradykinin antagonists (Bradykinin is a nonapeptide)
O
Iosciamine
Fine presentazione
Norbuprenorphine, the active dealkylated metabolite of buprenorphine
H
N
N
H
H
OH
H
HO
HO
O
OH
O
OCH3
OCH3
Norbuprenorphine has a slightly
different binding profile to opioid
receptors and is a potent opioid
agonist.
The side of action of the major class of analgesics
CB2 and pain
Keratinocytes are the most abundant cell type of the epidermis, the outer layer of the skin.
They have a pivotal role in mechanical and immunological protection of the organism and they were
also shown to contain CB2 and -endorphin.
Agonists acting at the CB2 receptor cause antinociception, but the mechanism of this effect
was not known. In their recent study, Ibrahim et al. now show that activation of the CB2 receptor
leads to the release of the opioid peptide, -endorphin.
-endorphin activates the m-opioid receptor and this activation, in turn, leads to the mitigation of pain.
The 5-(3-hydroxy)phenylmorphan class of opioids
(3-(2-azabicyclo[3.3.1]nonan-5-yl)phenol, 1a, Figure 1)
was originally synthesized over 50 years ago by May and Murphy.
The molecular conformation of the 5-(3-hydroxy)phenylmorphan is different from that of the morphinans,
4,5- epoxymorphinans and 6,7-benzomorphans, because its phenolic ring is equatorially oriented on the piperidine
ring, not constrained axially as in these other classes of opioids.
Many 5-(3-hydroxy)phenylmorphan derivatives show opioid-like in vitro and in vivo activities, and others are
opioid antagonists. The 1S, 5R enantiomer of 1b (Figure 1) was a fairly potent µ-, d-, and k-opioid antagonist,
more potent than the 1R, 5S enantiomer that was found to be a µ- and k-antagonist.
The different spatial positions of the aromatic rings of the phenyl-morphans and the morphinans and the wide-range
of molecular structures that interact with the µ-opioid receptor have made it difficult to find a reasonable
hypothesis that could relate their molecular structures to pharmacological activity either quantitatively
or qualitatively.