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Phyto Lec 16
Morphine is a demethylated codeine; then the morphine will be glucuronated
to the morphine 3-O-glucuronide and morphine 6-O-glucuronide. (the
%of codaine that is metabolized is not 100%)
Papaverine : is benzylisoquinoline alkaloid with no
any analgesic activity, has been used for male
impotance, being administered by direct injection to
achieve erection of the penis, but its not used any
more. Possesses spasmolytic and vasodilator activity.
Noscapine: Its original name ‘narcotine’. Has good
antitussive and cough suppressant activity. , they found that noscapine may
have teratogenic properties which resulted in noscapine preparations being
withdrawn. In recent studies, antitumor activity has been noted from
Papaveretum: mixture of purified opium alkaloids, contains only morphine
(85.5%), codeine (7.8%), and papaverine (6.7%). Used for pain relief during
operations, and cancer.
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The most modified compound is morphine; because we need its analgesic
effect as well as we'd like to avoid the addiction effect.(to reduce side effects)
semi-synthetic or totally synthetic morphine-like derivatives “opioids”
2 types of compounds; either semi-synthetic from morphine structure by
1)replacing OHs on the 3&6 positions most properly get morphine agonist
"with similar activity, lower side effects, more potent than morphine"
or 2)substituting on N most properly get morphine antagonist.
Here we have new terminology mixed morphine agonist antagonists which
have the same analgesic activity of morphine at the same time it counteracts
effect of morphine itself. And this term is only found in morphine. These drugs
are very important for the treatment of addiction of morphine or its
derivatives like heroin.
In other words; the mixed agonist antagonists have all the effects of morphine
and its antagonist, so its important to be in the transitional state so its not a
pure antagonist yet.
Many compounds have similar narcotic and pain-relieving properties as
morphine, but have less addiction capability.
Others possess the cough-relieving activity
of codeine, but without its analgesic effect.
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Has similar activity to codeine; effective and reliable antitussive.
2.Dihydrocodeine: similar analgesic properties of codeine,(the double
bond not essential for activity)
3.hydromorphone: the double bond of morphine has been reduced,
and the 6-hydroxyl has been oxidized to a ketone as well. This
increases the analgesic effects [agonist] as well as the side-effects.
4.Heroin: is a highly addictive analgesic and hypnotic.
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Was first developed as antitussive drug. simply manufactured, its Di-acetated
of morphine,. This make it more lipophilic and easier to cross the BBB.
It is at least 100 times more potent than morphine; and the tendency to cause
addiction is also 100 times !!! The euphoria induced by injection of heroin has
resulted in much abuse cases, and resulted in a world-wide major drug
problem. Fortunately it is very expensive drug!
It was widely used for palliative care, e.g. cancer patients, used as an analgesic
and cough suppressant.
Heroin effect lasts for >3 hours, however the effect of morphine lasts only for
1 hour.
mixed agonist–antagonist
The N-methyl group of morphine can be removed by treatment with cyanogen
bromide, then hydrolysis.
Nalorphine: has some analgesic activity,
it was used as antidote to reverse the
opioid overdose. it doesn't cause addiction.
(allyle group instead of the methyl)
Apomorphine: boiling with HCl. has no
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analgesic properties, but morphine’s side-effects of nausea and vomiting are
highly emphasized. Has a powerful emetic, and can be injected for emergency
treatment of poisoning.
Apomorphine’s structure contains a dihydroxyphenylethylamine
(dopamine) fragment, conferring potent dopamine agonist properties to this
Apomorphine is also valuable to control the
symptoms of Parkinson’s disease, as it's an
agonist of D1 and D2 dopamine receptors.
The natural pain killers (agonists) in the saliva
are 1000 time more potent than morphine.
The natural agonists include
peptides called enkephalins, Metenkephalin and Leu-enkephalin,
produced from a larger peptide
The 3D disposition of the nitrogen in morphine and other natural analgesics is
identical >>>> the N is very imp for the analgesic activity and the binding to
opioid receptors.
remember that, the dopamine receptors are responsible for the euphoretic
For Optimum Analgesic Activity
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1. Tertiary nitrogen (small groups)
2. Central Carbon atom, one H
3. Phenyl or a group isosteric with
phenyl connected to central carbon
4. 2-Carbons chain separating the
nitrogen from central carbon Page 5
Phyto Lec 16
Totally synthetic opioid drugs
levomethorphan and dextromethorphan:
Removal of the ether bridge and the
functionalities in the cyclohexene ring. Has
analgesic properties, whilst both enantiomers
possess the antitussive activity of codeine.
Pentazocine and phenazocine: the ether
bridge has been omitted and the cyclohexene
ring has been replaced by simple methyl groups. The methyl on the N is
replaced with a bulky group. These drugs are good analgesics and are nonaddictive, although pentazocine can induce withdrawal symptoms.
more drastic simplification of the morphine structure is found in pethidine
(meperidine), one of the most widely used synthetic opiates. Only the
aromatic ring and the piperidine systems are retained. Pethidine is less potent
than morphine, but produces prompt, short-acting analgesia (DOC in
hospitals), is also less constipating than morphine. It can be addictive.
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Fentanyl has a 4-anilino- rather than a4-phenyl-piperidine structure, and is
50–100 times more active than morphine due to its high lipophilicity and
excellent transport properties. It is rapid-acting and used during operative
Methadone is orally active, has similar activity to
morphine, but is less euphorigenic and has a longer
duration of action. Used for treatment and
rehabilitation of morphine and heroin addiction
before the pure antagonist.
Dextropropoxyphene has analgesic effect and found in combination with
aspirin or paracetamol. Unfortunately it was abused and withdrawn from the
-the international regulations and restrictions only for morphine; other
derivatives can be found in some countries while restricted
in others.
Tramadol is a recent drug (4-5years) claimed to produce
analgesic by an opioid mechanism and by enhancement of
serotoninergic and adrenergic pathways, with few typical
opioid side-effects. It causes addiction, So it is restricted.
-Note that the N is always presented.
Etorphine is some 5000–10 000 times more potent
than morphine. Used in veterinary practice to sedate
large animals.
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Diphenoxylate (Lomotil)
Can be OTC drug now. used as antidiarrheal drug. Has very little analgesic
properties at therapeutic dose. No antitussive activity.
At high doses it has analgesic problems? as it Causes respiratory depression
and euphoria at high doses.
Pure Antagonists
Antagonists: substitution on the nitrogen atom of an agonist.
Naloxone: potent antagonist, is used to treat opiate poisoning, including
those children of heroin addicts. Deprived from any analgesic effect. Occupy
the opiate receptors.
Naltrexone: it has isopropyl group.
It’s a long-acting pure antagonist and blocks every opiate receptor. There is no
analgesic or addiction effect.
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Phenethylisoquinoline Alkaloids
Phenethylene structure gives new compounds,
rearrangement results in a new ring called tropolone ring
7 membered ring, found only in one plant Colchicum
autumnale from the lily family (Liliaceae).
The active constituent is the Colchicine.
Colchicine is used for the treatment of hay fever,
Mediterranean fever, anti-inflammatory for gout
(does not affect uric acid metabolism).
Gout is the accumulation of uric acid in the
joints. Uric acid is formed from the xanthine by the xanthine oxidase enzyme.
The only drug that work on this mechanism is the allopurinol (a xanthine
oxidase inhibitor).
Colchicine is an effective treatment for acute attacks, but it is very toxic, and
this restricts its general use.
Colchicine binds to tubulin in the mitotic spindle, preventing polymerization
and assembly into microtubules >>> potential anticancer activity. But the
therapeutic index is very narrow, not allowing the use of it as anticancer
agent! (very high doses is needed)
GM : genetically modified
Polyploids multiplication of chromosomes in the cell nucleus without the
process of cell division.>>>> increase the productivity.
Colchicine is GM with other plants to produce polyploids. This doesn’t affect
the plant itself; but Colchicine given for hay fever, Mediterranean fever, antiinflammatory for gout for long life; really affect the patient.
During pregnancy if it is given it causes chromosomal division without cell
division leading to teratogenic effect (Down Syndrome).
Colchicine must be stopped (he or she) at least 6 months before thinking of
getting a baby.
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