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Phyto Lec 16 Opiates Non morphinan Morphinan Morphine Codaine Thebaine Papaverine Noscapine Papaveretum 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 , they found that noscapine may have teratogenic properties which resulted in noscapine preparations being withdrawn.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 noscapine. 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. Hiba Tarek Page 1 Phyto Lec 16 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. Hiba Tarek Page 2 Phyto Lec 16 1.Pholcodine: 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. Hiba Tarek Page 3 Phyto Lec 16 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 Hiba Tarek Page 4 Phyto Lec 16 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 agent. 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 endorphin. Enkephalin 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 effect. For Optimum Analgesic Activity Hiba Tarek 1. Tertiary nitrogen (small groups) 2. Central Carbon atom, one H Connection? 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. Hiba Tarek Page 6 Phyto Lec 16 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 procedures. 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 market. -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. Hiba Tarek Page 7 Phyto Lec 16 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. Hiba Tarek Page 8 Phyto Lec 16 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. Hiba Tarek Page 9