Opioid Analgesics PDF

Opioid Analgesics Patrick G L. Introduction to Medicinal Chemistry. 20 1 13. p. 623 Opioid Analgesics At the end of this chapter you will be able to Understand what is opioid Learn about opioid classification Understand Structure activity relation ship of opioid Learn about miss us...

Opioid Analgesics Patrick G L. Introduction to Medicinal Chemistry. 20 1 13. p. 623 Opioid Analgesics At the end of this chapter you will be able to Understand what is opioid Learn about opioid classification Understand Structure activity relation ship of opioid Learn about miss use and treatment of opioid overdose Patrick G L. Introduction to Medicinal Chemistry. 20 2 13. p. 623  Opioid Analgesics Opioids are a broad group of pain-relieving drugs that work by interacting with opioid receptors. Opioids can be obtained from the poppy plant or synthesized in a laboratory for example, fentanyl When opioid medications travel through the blood and attach to opioid receptors in the brain cells, the cells release signals that muffle the perception of pain and boost feelings of pleasure. What makes opioid medications effective for treating pain can also make them dangerous. At lower doses, opioids may make feel sleepy, but higher doses can slow breathing and heart rate, which can lead to death. And the feelings of pleasure that result from taking an opioid can make to continue experiencing those feelings, which may lead to addiction. Patrick G L. Introduction to Medicinal Chemistry. 20 3 13. p. 623  Terms and Definition Opiates are narcotic analgesics that are related to morphine in structure. Opioids are molecules either synthetic, semisynthetic, naturally occurring or endogenous that can interact with opioid receptors in the body and alleviate the pain Orphan receptor is a novel receptor in which ligand binding to it still not known. 4 History of opium and morphine The first opioid compound was extracted from opium. It is obtained from the sticky exudate from opium poppy (Papver somniferum). It is used as sedative and for treatment of diarrhoea. It was used by Royal British Navy as sedative during sailing. Famous nineteenth-century authors and poets have taken opium in regular basis and were addicted to it. Some communities started to smoke it especially in China. Due to problems associated with it, it was restricted in the twentieth century for medical and scientific purposes. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 632 5 www. google.com/images  Opium contain more than 20 alkaloids, however the active alkaloid in it is morphine. Morphine extracted in 1803 and then isolated and purified in commercial scale in 1833 by chemists from Macfarlane- Smith firm in Edinburgh. It used in medicine when the syringe was invented in 1853. Morphine revealed that it is a potent analgesic and sedative. Risks were associated with it are addiction, tolerance and respiratory depression. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 632-633 6  Structure and Properties of Morphine At the time of the isolation of morphine, it was a challenge to identify the structure. Usually chemists used to degrade compounds into smaller compounds that are already known. In 1925, Sir Robert Robinson proposed a structure for morphine. The synthesis of this structure was done in 1952 and it is proven by X-ray crystallography in 1968. Morphine contains five rings labelled A-E and has T- shaped structure. It contain tertiary amino group, phenol, alcohol, aromatic ring, ether bridge and alkene double bond. It is consider basic compound because of the tertiary amino group The nitrogen atom can undergo inversion as it can convert between the axial and equatorial positions. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 632-633 7  Opioid Receptors Opioid receptors are available in the CNS that lead to reduction in the pain signals to the brain. There are three main receptors for opioids, mu(µ), kappa (ĸ) and delta (δ). Also, there are new names for these receptors, MOR, KOR and DOR receptors. A fourth type of receptors also now has been discovered called (opioid receptor-like receptor) (ORLI). It is now known as NOR. It is a type of orphan receptors as the endogenous ligand that bind to it not known. Opioid receptors are G-protein-coupled receptors which activate Gi or Go signals. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 636 8 Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 634 9 Activation of opioid receptors by morphine has different effects Mu Kappa Delta receptors receptors receptors Potent Less Less analgesia analgesia analgesia Dangerous Side Does not side effects cause effects as such as sedation, respiratory anxiety, euphoria, depression depression or physical , euphoria, and dependenc addiction psychosis e and physical dependenc e Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 636 10  SAR of Morphine Important groups for analgesic action of morphine are  phenol OH group Aromatic ring Tertiary amine Relative position of functional groups  Contain five asymmetric centers at C5, C6, C9, C13 and C14. However the natural morphine is available as single stereoisomer. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 634-635 11  Changing the stereochemistry of one asymmetric center result in decrease in activity. There are doubt about the importance of OH group when the drug come to in vivo as the pharmacokinetics affect the activity The OH group can undergo metabolic conjugation when it reach to the body easily which will affect their bioavailability to CNS rather their important binding interactions that can do it. Masking of OH group or missing it will lead to increase their hydrophobicity and so molecules can cross BBB easily. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 635 12  Pharmacokinetics of morphine Morphine is injected as intravenous injection because it is relatively polar in order to prevent its metabolism. The amine group is consider as weak base, so it can exit as a free base and ionized from. The free base can cross BBB and then protonated to interact with the receptor. The pKa is 7.8 – 8.9 for useful analgesics. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 636-637 13  Morphine analogues Oxymorphone Modification of hydroxyl group at position 6 increases the activity Introduction of a hydroxyl group at position 14 increases the activity than morphine Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 634, 638 14  6-acetyl morphine Heroin To increase the level of morphine in Acetylation of the phenol and the brain, some polar groups are hydroxy group result in a masked. compound called diamorphine Acetylation of the hydroxy group at (heroin) position 6 result in a compound called 6-acetyl morphine. It 2 fold more active than It is four times more active than morphine morphine and more dangerous Patrick G L. Introduction to Medicinal Chemistry. 20 15 13. p. 637 Oxycodone  N-phenylethylmorphine Modification at positions 3, 6 and 14  Larger alkyl groups than methyl at nitrogen increases the analgesic activity than position decreases the activity morphine  The activity retained with larger groups such as pentyl or hexyl  Groups like phenyethyl increases the activity and suggest that there is a hydrophobic binding site Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 638-639 16  Removing ring E lead to loss in activity which mean that the basic nitrogen is important to activity Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 640 17  Morphinans Removing ring D lead to series of compounds called morphinans levorphenol are more potent than morphine and with long duration of action but with more side effects Adding an allyl group gave an antagonist that is more potent than nalorphine Adding a phenylethyl group increases the potency than morphine Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 640 18  Benzomorphans  Removing ring C and D lead to a serious of compounds called benzomorphans  Metazocine contains two cis methyl groups that are important for analgesic activity  Replacing N-methyl group of metazocine with phenylethyl lead to phenazocine with good analgesia and without dependence Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 623 19  Benzomorphans  Pentazocine has very potent analgesic activity and low risk of addiction. It act as antagonist at mu receptors and agonist at kappa receptors. Also weak agonist at delta receptors. The compound has serious side effects as hallucination and psychotomimetic side effects  Bremazocine is with longer duration of action and more potency and does not depress breathing Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 641 20  Removing rings B, C and D lead to compounds called 4- phenylpiperidine  The activity is more than morphine due to the ester group  Ketobemidone has more activity as the ester changed to ketone  Pethidine (meperidine) has less analgesic effect than morphine but with rapid and short duration of action. It can be used in childbirth as it has less chance to depress breathing of child due to short duration of action  Replacing the methyl group of pethidine with cinnamic acid results in more potent analgesic than morphine. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 642 21  Another type of opioid analgesics are 4-anilinopiperidine (Fentanyl and its analogues)  Very potent  They lack phenolic group, which suggest that phenolic group is not necessary for analgesic activity while aromatic ring and basic nitrogen are essential  Are lipophilic, so they can cross BBB. Thus it can be used in surgery  Remifenatnyl with very short duration of action due to hydrolysis by esterases which make it with less side effects. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 642 22  Removing rings B, C, D and E lead to the discovery of methadone  It is used as alternative for drug addiction for morphine and heroin  It is a diphenylpropylamine structure that contain an asymmetric center  One of the side effects of opioid analgesics is constipation  Linking methadone with 4-phenylpiperidine produce an antidiarrhoea agent (loperamide). It act as selective agonist on opioid receptors in the GIT. It is lipophilic, slowly absorbed and can be metabolized easily. Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 643-644 23  Previous structures of morphine analogues are flexible molecules that may adopt many conformations. In order to decrease these conformations, the strategy of rigidification had been used to limit the number of conformations. This may increase selectivity, potency and decrease side effects  Orvinols (oripavines) are type of compounds that has been used by this strategy  Examples of orvinols are etorphine, dihydroetorphine, diprenorphine and buprenorphine Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 644-645 24  Etorphine is 10,000 times potency than morphine due to the lipophilic group at position C20 which may increase the binding interactions with the receptors. It is used as to immobilize large animals such elephants  Dihydroetorphine is 10 fold potency of etorphine.  Diprenorphine is a pure antagonist at mu receptors, due to addition of cyclopropyl group at N-substituent. It is 100 times potent than nalorphine. It can be used to reverse the effects of etorphine.  Buprenorphine is partial agonist at mu receptors and an antagonist at kappa and delta receptors. It is more lipophilic than other orvinols. It has less side effects on respiration Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 645-646 25  Morphine antagonists The addition of an allyl and cyclopropyl to nitrogen side chain to oxymorphone result in a compounds without analgesic activity. They bind to morphine receptors and act as antagonists This useful in case of morphine overdose, morphine addict and alcoholism. Administering naloxone and nalorphine in morphine overdose, block morphine from binding to its receptor and prevent patient death from suffocation due to respiratory depression. Naltrexone used in case of morphine or heroin addict. Nalmephine used in case of alcoholism as block opioid receptors and prevent the release of endogenous opioids as a result of drinking. Nalorphine is antagonist at mu receptors and agonist at kappa receptors which provide a safe analgesia but it have undesirable side effects as hallucinogenic and psychosis due to activation of kappa receptors. Patrick G L. Introduction to Medicinal Chemistry. 26 2013. p. 638-640 Morphine antagonists Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 638-640 27  Endogenous Opioid Peptides Endogenous chemicals that interact with opioid receptors are enkephalins There are two types of enkephalins: Met-enkephalin and Leu- enkephalin Now there other peptides (neurotrasnsmitters or neurohormones) that act as neutral painkillers consist of 5-33 amino acids. These are:  enkephalin, the precursor is proenkephalin Endorphin, the precursor is prodynorphin Dynorphins, the precursor is pro-opiomelanocortin Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 649-650 28  Endogenous Opioid Peptides Other endogenous peptides that had been discovered are:  nociceptin or orphanin-FQ  They are ligand for ORLI-receptor  They are heptadecapeptides and contain phenylalanine at N-terminal  Endomorphins  Are tetrapeptides that have affinity for mu receptors Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 650 29 Binding of enkephalins Enkephalins interact with two binding regions Phenol of tyrosine interact with T- binding region Phenyl ring of phenylalanine with P- binding region There is also the ionic-binding region Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 652 30  Message-address concept Enkephalins have preference to delta receptors Dynorphins have selectivity for kappa receptors Endorphins have selectivity for mu and delta receptors These differences in selectivity for analgesic receptors led to a theory called message-address concept It propose that part of the molecule is responsible for pharmacological activity (the message) and another part is responsible for target selectivity (the address). It could be a function group that can interact with one type of receptor It could a feature that can act as a steric shield and prevent the molecule from binding to some receptors but not the others Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 650, 653-654 31 Analogues of enkephalins and delta-selective opioids Enkephalin can be metabolized by peptidases between the bond of tyrosine and glycine To make enkephalin resistant to hydrolysis, analogues can be designed by:  replacing one or both of glycine units by D-amino acids such as D-alanine N-methylating the peptide bond can block peptidase hydrolysis Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 650-651 32  Naltrindole is a selective antagonist of delta receptors  It is developed by fusing an aromatic ring to the C-ring of naltrexone a non-selective delta antagonist.  The aromatic ring will act as the message for delta receptors  It is found that conformation that have adopted by leu-enkephalin (an endogenous opioid) during interactions with delta receptor is similar to that of naltrindole Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 651 33 Instruction: Circle the letter of the best answer. Morphine contains tertiary amino group, phenol, alcohol, aromatic ring and ether bridge. It is considered basic compound because of the.1 a.alkene double bond.a b. tertiary amino group c. phenol group d. ether bridge Morphine contains five rings labelled A-E and has.2 a. Y-shaped structure b. L-shaped structure c. T-shaped structure d. D-shaped structure In morphine, extension of N- methyl to N-ethyl or N-propyl, make the compound.3 a. extremely high agonist b. extremely high antagonist c. weak agonist d. none of the above Morphine is an important analgesic. The interactions that are involved in binding of the phenol group to the target binding site is.4 a. ionic interaction b. hydrogen bond c. covalent bond.d Patrick G L. Introduction to Medicinal Chemistry. 20 34 13. p. 623 5. Methylation of the phenolic OH in morphine gives a. codeine b. heroin c. levorphanol d. Methadone Codeine is used as an analgesic. Codeine.6 a. is stronger analgesic than morphine b. binds strongly to the receptor through the N group c. is weaker analgesic than morphine d. is more acidic than morphine A molecule with the following structure is more active than morphine as an analgesic. The name of this molecule is.7 b. methadone c. heroin d. levorphanol Patrick G L. Introduction to Medicinal Chemistry. 20 35 13. p. 623  The reaction that involve conversion of compound 1 to 3-monoacetylmorphine is.8 AcO a. deacetylation AcO b. acetylation c. decarboxylation O d. Dealkylation O N N CH 3 CH3 HO AcO Endomorphine – 1 and Endomorphine – 2 are endogenous tetra peptide with.9 3-monoacetylmophine a. low degree of selectivity for Mu (µ) receptors Compound 1 b. affinity for mu receptors c. high affinity for Delta (∆)receptors d. high affinity for Kappa (К) receptors The activity of morphine will.10 a. increase if the aromatic ring is reduced b. increase if the C7=C8 bond is reduced c. abolish if the aromatic ring is removed d. b and c Removal of the ether bridge from morphine structure will.11 a. give compounds called morphinans b. enhance antagonistic activity c. make the compound more hydrophilic d. decrease the analgesic activity Patrick G L. Introduction to Medicinal Chemistry. 20 36 13. p. 623 For morphine, it is possible to separate the analgesic activity from addiction potential by the.12 a. removal of the c ring b. reduction of the C7= C8 double bond c. acetylation of the phenolic OH d. change of an N – methyl to an N – allyl group Pethidine (meperidine) is.13 a. 4-phenylpiperidine b. morphine from which ring B, C and D has been removed c. 4-cyclohexanopiperidine d. a and b Fentanyl and its analogues.14 a. are 4-anilinopiperidine derivatives b. lack the phenolic group c. are lipophilic, so they can cross BBB d. all of the above Fentanyl 15. Which of the following are natural opioids? a. Morphine b. Oxycodon c. Codeine d. a & c Patrick G L. Introduction to Medicinal Chemistry. 20 37 13. p. 623 For morphine, it is possible to separate the analgesic activity from addiction potential by the.12 a. removal of the c ring b. reduction of the C7= C8 double bond c. acetylation of the phenolic OH d. change of an N – methyl to an N – allyl group Pethidine (meperidine) is.13 a. 4-phenylpiperidine b. morphine from which ring B, C and D has been removed c. 4-cyclohexanopiperidine d. a and b 15. Which of the following are natural opioids? a. Morphine b. Oxycodon c. Codeine d. a & c Patrick G L. Introduction to Medicinal Chemistry. 20 38 13. p. 623  The following molecule (etorphine) is used in veterinary medicine for.18 a. sedation b. treatment of diarrha c. constriction of the pupil d. Inflammation Linking methadone with 4-phenylpiperidine produce an antidiarrheal agent called.19 a. fentanyl b. loperamide c. pethidine d. hydromorphone Naltrindole is a selective antagonist of delta receptors. The ring that is fused to the C ring is.20 a. naphthalene b. imidazole c. indole d. piperidine ring Patrick G L. Introduction to Medicinal Chemistry. 20 39 13. p. 623  2 3 Section 11: Short Answer Questions (SAQ) [10marks] 1.You are given the structures of levorphanol.1 11 4 12 10 15 16 13 5 14 9 6 8 7 1.1 Indicate the chiral centers. [3 marks] 1.2 Which ring is removed from the structure of morphine to give levorphanol? [1 mark] 1.3 Levorphanol is more potent than morphine. Explain [ 1 mark] 1.4 What alkyl group on the nitrogen will increase the activity 14 times? [1 mark] 1.5 What alkyl group on the nitrogen will change it to mu antagonist? [1 mark] Patrick G L. Introduction to Medicinal Chemistry. 20 40 13. p. 623  Name Chemical class 2.2 Patrick G L. Introduction to Medicinal Chemistry. 20 41 13. p. 623 Patrick G L. Introduction to Medicinal Chemistry. 20 42 13. p. 623