Opioid Analgesics PDF

1 What do you want to know  What opioid analgesics are?  Mechanism of action  Their receptors  SAR and development of other analgesics  Metabolism 2  Opiate/ Opioid “Opiate” (used until 1980s) means drugs der...

1 What do you want to know  What opioid analgesics are?  Mechanism of action  Their receptors  SAR and development of other analgesics  Metabolism 2  Opiate/ Opioid “Opiate” (used until 1980s) means drugs derived from opium – morphine, codeine, and their semi synthetic analogs (Natural or semisynthetic) Opium - is a Greek word meaning “juice,” or the extract of seeds from the poppy Papaver somniferum Opiates: Synthetic/ natural compounds both structurally and pharmacologically similar to Morphine Morphine was the first Narcotic analgesic isolated from opium which contains over twenty distinct alkaloids Opioids: Any drug which binds to the opioid receptor in the CNS and antagonized by Naloxone. They may be – Morphine Natural, Synthetic and semisynthetic. Opioids: Synthetic/ natural compounds not structurally but only pharmacologically similar to Morphine 3 Opioids - Opium Friedrich Wilhelm Serturner; A German Pharmacist– Isolated Morphine in 1803 and named it after the Greek god of Dreams “MORPHEUS” 4  Uses Choice of drugs for managing chronic pain as with cancer or RA Used as inducing agent (fentanyl) or analgesic supplement with General anesthetics They have clinical use as anti-diarrheal and antitussive eg. Loperamide and Dextromorphan Some opioids such as methadone and buprenorphine are used to counter addiction of more potent opioids such as heroin 5 Analgesic receptors (G-protein linked receptors) Body hasmechanism to naturally relief pain Opioid receptors found in CNS, Peripheral nervous system (PNS), and GIT. There are three types in brain and spinalcord µ (mu) --> most widely occurring and target of most drugs Κ (kappa) --> lack respiratory depressing effect and can counter analgesic effect of µ agonist (safest) δ (delta) --> reduced GIT motility, respiratory depression, convulsant effect limited clinicaluse Only µ and Κhave clinicaluse 6  Analgesicreceptors (G-protein linked receptors) Receptor type Location Effects μ Brain, spinal cord Analgesia, respiratory depression, euphoria, addiction, ALL pain messages blocked κ Brain, spinal cord Analgesia, sedation, all non- thermal pain messages blocked δ Brain Analgesia, antidepression, dependence ❖ In general, opioids act upon mu-, delta-, and kappa-receptors on CNS neurons producing: Analgesia via decreased neuronal transmitter release and decreased nociceptive impulse propagation Appears to work by elevating the pain threshold, thus decreasing the brain’s awareness of pain 7 Opioids - Classification 1. Natural Opium Alkaloids: Morphine, Codeine, Thebaine and papaverine 2. Semi-synthetic: Buprenorphine, Oxycodone (hydromorphone), Diacetylmorphine (Heroin( 3. Synthetic Opioids: 4-Phenylpiperidines: Loperamide and Fentanyl, Pethidine and Meperidine Diphenylpropylamine derivatives: Loperamide, Methdone and dextropropoxyphene Benzomorphans: Pentazocine, Phenazocine Morphinan : Levorphanol and Butorphanol 4. Endogenous opioid : natural pain relieving peptides of the body, such asendorphins, enkephalins and dynorphins 5. Miscellaneous : Tramadol, Meptazinol 8  Classification 2. According to Potency Strong agonist Morphine morphine, heroin, meperidine, methadone, fentanyl Moderate agonist codeine, propoxyphene. Mixed agonist-antagonist buprenorphine, pentazocine Antagonist: naloxone, naltrexone 9 Naltrexone  Morphine  Morphine is the principal alkaloid inducing analgesic  Morphine is poorly absorbed orally  Side Effects: Respiration depression, Constipation, Euphoria, Tolerance, Dependence, Nausea, Pupil constriction  Five rings (A, B, C, D, and E).  T-Shape drug  Basic due to tert-amine  Contain phenol, alcohol and ether , Alicyclic unsaturated linkage Structure (1923) 10  Numbering of morphine is based on phenanthrene. The important positions 3, 6, 7, 8,14 are indicated. 11  Potential Binding HO Groups O Phenol NMe HO Ether Alcohol Amine Potential Binding Groups ✓ Functional groups are present capable of forming ionic, hydrogen bond and van der Waals interactions ✓ Carbon skeleton – capable of forming van der Waals interactions 12 Potential Binding HO Groups O Phenol NMe HO Aromatic ring Ether Alkene Alcohol Amine 13 Functional groups – Necessary Phenolic OH for (hydrogen bonding) Tertiary amine for (ionic bond) Aromatic ring for (Van de Waals bonding) 14 Structure Activity Relationships  Mask or remove a functional group  Test the analogue for activity  Determines the importance or otherwise of a functional group for activity 15 SAR: Modification to Morphine 1- Morphine has 5 Chiral centers. Only the Levo (-) rotatory isomer is active 2- The OH group in the phenolic ring and basic Nitrogen is needed for activity and seen in all potent µ agonist. 3- Activity can be preserved or enhanced by removing other rings 4- Changing -OH to just –H or -OCH3 lowers activity as seen with codeine R= C3 Activity effect substituent -H 10 X Decrease -OH morphine -OCH3 Decrease )codeine) 16  Morphinans Benzomorphine 4-Phenylpiperidines Fig: Loss of other rings doesn’t effect analgesicactivity. How many chiralcentres? Morphinans Morphine 17 5- The Nitrogen is mostly tertiary with a methyl substitution in morphine. The size of substituent on Nitrogen dictates potencyand agonist or antagonistactivity. a) Increasing size from methyl (ie 1 C) to 3 or 5 carbon (especially with double bonds or small cyclic/ aromatic rings) results in antagonist activity b) Still larger substitution restores agonist activity in more potent form Morphine Naloxone Naltrexone 18  If R= 3-5 carbons then µ antagonisteffect (more valid if presence of double bond or Small carbon-cyclic ring If R= > 5 carbon (in chain or ring ) then increased µ agonist effect R= Nitrogen effect subtituent CH2CH=CH2 Becomes µ antagonist (3 Cwith double bond) CH2CH2Ph µ agonist (10 X more )Total 8 C) potent than morphine( 19 Naloxone ❑ Reduction of 7,8 double bond increases activity ❑ Inclusion of Hydroxyl group at 14 increases activity Activity Activity increases increases 7,8 Reduction of double OH at C14 bond to single bond 20 6. Removal of Hydroxyl at 6 increasesactivity 7. Oxidation of Hydroxyl to keto group at 6 increases activity, if there is also reduction of 7,8 double bondeg. hydrocodone 8. Acetylation of Hydroxyl at 6 increases activity R= C6 substituent Effect in activity H increase =O (keto) Decreases =O (keto) with 7,8 redcution Increases (10 X more potent (change double bond to than morphine( single) H3CC=O (acetyl) Increase 21 9. Removal of the ether linkage produces compounds called morphinans that has increases activity No ether linkage Activity increases Levorphanol (10X potent than morphine) 22 23  The phenol moiety Codeine is metabolised in the liver to morphine. The activity observed is due to morphine. RO Codeine is used for mild pain and coughs Weaker analgesic but weaker side effects. O Conclusion: Masking phenol is bad for activity NMe R= H= Morphine R= CH3= Codeine HO HH R=Ac 3-Acetylmorphine-------Decreased activity Acetyl masks the polar phenol group Compound crosses the blood brain barrier more easily Acetyl group is hydrolysed in the brain to form morphine HO 6- Position, R=Me Heterocodeine- 5 x activity O NMe RO HH HO HO HO O O O NMe NMe NMe HO O Activity increases due to reduced polarity Compounds cross the blood brain barrier more easily 24 6-OH is not important for binding The 6-alcohol HO R=Ac 6-Acetylmorphine---Increased activity (4x) O H NMe H RO Acetyl masks a polar alcohol group making it easier to cross BBB Phenol group is free and molecule can bind immediately Dependence is very high 6-Acetylmorphine is banned in many countries R=Ac Heroin----Increased activity (2x) Increased lipid solubility Heroin crosses the blood brain barrier more quickly Acetyl groups are hydrolysed in the brain to generate morphine 25 Fast onset and intense euphoric effects Double bond at 7,8 HO Dihydromorphine----Increased activity O The alkene group is not important to binding H NMe H Nitrogen HO No activity Nitrogen is essential to binding 26  Methyl group on nitrogen NR= NH Normorphine HO Reduced activity (25%) + NR= NMe - O O No activity H NR NR= N+Me2 H No activity HO Normorphine is more polar and crosses the BBB slowly Ionised molecules cannot cross the BBB and are inactive Ionised structures are active if injected directly into brain R affects whether the analogue is an agonist or an antagonist27 Stereochemistry Morphine HO HO O O NR H NR H HH HO HO 10% activity Mirror image of morphine No activity Changing the stereochemistry is detrimental to activity 28  Stereochemistry of morphine Morphine is asymmetric with 5 chiral centres Naturally exist as a single stereoisomer The synthesised form, was made as a racemic mixture. The unnatural mirror image was not active This because binding interactions are not fully triggered to give analgesic activity. 29 SAR - Important binding interactions HBD or HBA HO van der Waals O H NMe H HO Ionic (N is protonated) 30 General – Morphine SAR and Analogues Aromatic ring (A) required for analgesic activity (phenolic OH, best activity when it is free) The amine (N), ring-E is essential for analgesic activity (the group attached determeines, agonist/antagonist activity) Ether bridge (Ring D) is not necessary for analgesic activity 6-hydroxyl, ring-C is not necessary for analgesic activity Double bond (7-8 pos.) several analogues: e.g. Dihydromorphine is not necessary for analgesic activity 31 Morphine It is anaturally occurring analgesic alkaloid extractedfrom opium of poppyplant Modification to it’s structurehasresulted more potent compounds Usedin chronic pain management It’s 3-O-glucoronidation metabolite isinactive But it’s 6-O-glucoronidation form is active and thus dose reduction is needed in caseof renal damage (coz it’s rate of clearance is reduced) It is potent enough that it’s 60mg oral dose has analgesic effect equal to parentaladministration. Morphine is poorly absorbed orally MOA: agonizes µ receptor which depresses pain signalsby inhibiting voltage gated calcium channels (VGCC)and prevent release of Neurotransmitters Opening voltage gated potassium channels (VGPC) and causing hyperporalization of nerves cells (Increases K+ outside the cell to cause hyper polarization of cell thus reducing it’s excitability) Inhibiting adenylyl acylase (implicated in memory formation, functioning as a coincidence detector) 32 Morphine Side Effects: Respiratory depression, Nausea and vomiting, Pupil constriction, Constipation, Euphoria, Itching and Tolerance and dependence (Addiction) The quaternary methiodide salt of morphine has no analgesic activity when injected into the blood supply, but it is active when injected directly into the brain. The salt is unable to cross the blood brain barrier - I + 33 Codeine Codeine is 3-methyl ether of morphine RO It is weak µ agonist formed by R=H Morphine R=Me Codeine modification of 3 OH in morphine into H3CO. This results in loss of activity. Thus codeine is used in moderate to O mild pain only. NMe H It is metabolic product is morphine and H thus abused by addicts. HO The dose requires to produce analgesia after parental dose causes release of histamine that in turn Codeine 20% active (injected causes allergic responses. Thus not used peripherally) parenterally 0.1% active (injected into brain) 34 Uselimited as antitussive drug Heroin It is 3,6- diacetyl derivative of morphine By itself is a weak µ agonist but the diacetyl form increases its lipophilicity and enhances its penetration into brain Also it metabolic product, 6- acetyl morphine, is more active than morphine These two factors make it more potent than morphine but it’s use it limited by extreme addiction to it (more potent = more addictive) 35 Meperidine (Pethidine) It is a 4-Phenylpiperidines based derivativeof morphine Aweak µ agonist, 1/10th aspotent as morphine Less potency and shorter duration Activating opioid receptors, particularly κ receptors Doesn’t inhibit cough Rapid onset of action but high 1st pass metabolism (Duration of action?) Thus used in obstetrics, where given in small does to mother it won’t causerespiratory depression to thenewborn???? 36 37  Methadone 1. Analgesic effect is equal to morphine in potency Longer duration of action (t1/2 37 h) more effective in oral administration than morphine. Less problems with withdrawal Physical dependence occurs slowly 2. Use: Analgesia Suppression of withdrawal syndrome Treatment of heroin user. 38 Fentanyl It isa 4-(Phenylpropionamido)piperidines basedderivative of morphine It isabout 80 times more potent than morphine It Does not cause histamine release on IV injection (ie no skin inflammation) It Inhibits p-glycoprotein mediated efflux of digoxin (ie increases conc of digoxin inblood) Alfentanil Effects: Alfentanil has a more rapid onset of action. Shorter duration of narcotic effect than fentanyl. Uses: Adjunct to general anesthetics Alfentanil 39 Fentanyl Buprenorphine It hasamixedAgonist/antagonisteffect It produces 50% analgesic effect about 20-50 times than morphine but can NEVER produce 100% effect Potent Partial agonist of µ and κ receptor but antagonizes δ receptors Advantage of less severe respiratory depression and less incidence of tolerance or addiction Used to block effects of high dose of heroin Itself can’t be antagonized by Naloxone 40 Pentazocine A mixed agonist/ antagonist effect (µ antagonist and κagonist) Weak analgesic effect - 1/6 aspotentas morphine Since it is a K agonist it produces dysphoric effects and also increases blood pressure and heart rate Abused drug – when injected with tripelennamine (an antihistaminic) it increases euphoric effect and decreases dysphoriceffect 41  Tramadol Tramadol provides moderate pain relief, fast on set of action not atrue opioidanalgesic (Why?) Because of its dual actions as a µ-agonist and monoamine transport inhibitor, it produces less respiratory depression for a given analgesic effect. (+) isomer hasactivity 1/3800 that of morphine! (-)isomer blocks norepinephrine and serotonin (excitatory NT) reuptake and thus show some analgesic activity. But the effect is weak Tramadol is a weak agonist at µ-receptors and It’s metabolite is active (1/35 as effective as morphine). Less addictive, no respiratory depression or less constipation Used with other analgesic(Paracetamol)for synergistic effect In the body it is converted to desmetramadol, which is a more potent opioid 42  Dextropropoxyphene ❖ It is (t1/2 5 h) structurally similar to methadone ❖ Differs in that it is less analgesic and less dependence producing. ❖ Its weak μ/κ/δ-agonist ❖ Analgesics usefulness approximates to that of codeine, but its duration of action is longer. Methadone Dextropropoxyphene 43 Naloxone It is astrong opiodantagonist High affinity for µ but low affinity for κ and δ It is used as a emergency drug to counteract life- threatening depression of the CNS and respiratory system due to morphine or heroine overdose Itself is not anxiolytic but can potentiate the subtherapeutic dose of the anxiolytic drug busiprone (ie less dose of busiprone can begiven) Naloxone 44  Physical dependence/ Addiction to narcotics All forms of drug addiction are driven by stimulation of brain’s self-reward system Self reward system refers to activity of neurotransmitter Dopamine (DA) which has euphoric effect (intense feelings of happiness, excitement, and joy) Any Drug that concentrate DA in the synapse by – stimulate DA release, – Inhibit DAreuptake or – Inhibit DA degradation have addiction potential µ agonist stimulate release of DA, ie causes euphoria, whereas κ agonist prevent DA release ie causes dsyphoria (this effect limited its clinicaluse) Cocaine prevents reuptake of Dopamine at the synapse and thus prolong the duration and intensity of reward response 45  But the self reward system is self-limiting ie after prolonged or repeated activation feedback mechanism blocks the euphoric effect. Thus, the effect lasts for a short while But with opioids, the euphoric effect is very intense. This short but intense feeling of happiness is termed as “euphoric rush” and is veryaddictive. Drugs that slowly distribute to the brain have less addiction potential because the feedback system can respond quickly Only fast distributing drugs, that are potent too, are successful to causea “euphoric rush” Distribution into the brain is governed by the lipophilicity and thus abused drugs are very lipophillic to allow quick distribution and quickaction. Also route of administration is lungs or IV to cause quick distribution (thus oral dosage has lessaddiction potential) 46 Tolerence Tolerance means the need for higher doses to produce same level of effect When an agonist binds to µ receptor, – G second messenger proteins are activated – and adenyl cyclase are inhibited Oncontinuous binding, tolerance develops dueto – Decreases synthesis of G-protein subunits – Up regulation of adenyl cyclase to compensate the decreases cellular levels of cAMP. 47 Withdrawal Stopping intake of opioids produces unwanted physiological effects called withdrawal symptoms Within 24 hrs following effects are seen – muscle aches (pain), restlessness, anxiety, lacrimation (eyes tearing up) runny nose, excessive sweating, inability to sleep After 24 hrs more intense effects are seen – Diarrhea, high BP, nausea, vomiting, rapid heart beat Cells resist opioid mediated decrease in adenyl cyclase by upregulating (increases production) adenyl cyclase. If opioids are withdrawn, this up-regulated adenyl cyclase in turn generates more cAMP. This increased cellular levels of cAMP causes many 48 abnormal effects Endogenous Opioid Peptides Endorphins: Derived from Pro-opiomelanocortin (POMC( s-endorphins: 2 Types - s-endorphin-1 and s-endorphin-2 Primarily μ agonist and also has δ action Enkephalins: Derive from Proenkephalin Met-ENK and leu-ENK agonist Met-ENK - Primarily μ and δ agonist and leu-ENK – δ Dynorphins: Derive from Prodynorphin: DYN-A and DYN-B Potent κ agonist and also have μ and δ action 49 Opioid Antagonists 1. Pure antagonists: Naloxone, Naltrexone and Nalmefene Affinity for all receptors (μ, δ and κ) Can displace opioids bound to α-receptors Naloxone No action on Normal person but reverses poisoning and withdrawal symptoms in addicts 2. Mixed Agonist-antagonists: Nalorphine, Pentazocine, Butorphanol and Nalbuphine 3. Partial/ weak μ agonist and κ antagonist: Buprenorphine µ agonist promotes dopamine release that causesaddiction Naltrexone κ agonist blocks dopamine release leading to extreme depression that cancause suicidal tendency δagonist do notexist seemslike we are stuck with addictiveanalgesics!!! Nalmefene50  Drug extension – Morphine Antagonist HO HO O O N N OH O Naloxone OH Naltrexone HO Naloxone and Naltrexone Have no analgesic activity at all. Act as antagonist OH is critical for enforcing antagonism O Treat morphine overdose N HO Nalorphine Nalorphine (Mixed) Antagonist with week analgesic activity 51  How a drug is analgesic but antagonist at the same time? HO O N HO Nalorphine 1. Has weak analgesic activity and free of side effects? 2. How can a compound act as antagonist, but also act as agonist (analgesic activity). 3. The results observed from Nalophine show that activation of this third receptor leads to analgesia without the undesirable side effects?? 4. so the work now is how to design selective agonists for this receptor?? 52  Opioid Antagonist mixed agonist/antagonist pure antagonist OH The 14 hydroxyl group is believed to be important for the pure antagonist properties of these compounds?? 53  Why OH is important for antagonism? N-Phenylethylmorphine – (powerful agonist, Why???) Weak interaction or No interaction Strong interaction 54  Why OH is important for antagonism? Nalorphine – (mixed agonist and antagonist) Naloxone (Pure antagonist) The 14 hydroxyl group is believed to be important for the pure antagonist properties of these compounds 55  For the future Kappa-receptor specific agonists- reduced side effects Selectivity between mu-receptor subtypes: possibility of subtypes, one of which may lack side effects Peripheral opiate receptors-analgesics designed to target ileum receptors, bypass need to cross BBB Agonists for the cannabinoid receptor-these types of agonists may play a role in enhancing the effects of opiate analgesics, allowing less opiate to be administered 56  DRUG DESIGN OF OPIOID ANALGESICS Aims of opioid drug design To maintain activity To lower side effects To increase oral activity HO Extension O – Add extra binding groups NMe – Find extra binding regions HO – Increase activity 14 – Decrease side effects Extension at position 14 57  Extension at position 14 HO OXYMORPHINE 2.5 x activity O NMe OH O Possibly an extra hydrogen bonding interaction with the receptor through the 14-OH group  Extension - N-Substituents HO O NR N-Substituted morphines HO Synthetic method R-X 1)VOC-Cl 2) MeOH NMe NH NR Normorphine O Cl VOC-Cl = Vinyloxycarbonyl chloride O  HO Analogues O NR HO R= Me Et Pr Bu Amyl, hexyl CH2CH2Ph Activity drops No Activity 14x Activity Activity restored Conclusion Phenethyl substituent reaches a hydrophobic binding region Analogues HO O R= CH2-C=CH2 or CH2 NR HO Act as antagonists! Bind to receptors Fail to activate receptors Useful to counteract morphine overdoses Useful for treating drug addiction to morphine or heroin Examples of antagonists HO O N OH HO Naltrexone 8 x more active than Potent antagonist naloxone as an antagonist 2 x more active than Given to wean drug addicts nalorphine off morphine or heroin Nalorphine Examples of antagonists with agonist activity HO Nalorphine O N HO Antagonist Used to treat morphine overdose Weak agonist as well! Indication of multiple opioid receptors Antagonist at some (), agonist at others () Non-addictive analgesic First indication of a safe opioid analgesic Hallucinogenic side effects Examples of antagonists with agonist activity HO O Nalbuphine N OH HO Similar activity to morphine Low addiction liability No psychotomimetic effect Not orally active 55 Simplification Strategies Remove non-essential functional groups Remove excess rings Remove excess asymmetric centres Properties of simplified analogues Easier, quicker and cheaper to make May increase or decrease activity May interact differently with receptor May increase or decrease side effects Remove excess functional groups and ring D Morphinans HO NMe Levorphanol Morphinans HO NMe NMe Levorphanol N-Methylmorphinan 5x activity 20% activity (no phenol) Increased side effects Orally active Longer duration Less metabolism in liver Morphinans HO HO Ph N N Levallorphan N-Phenethyl levorphanol Antagonist 15 x activity of morphine 5 x nalorphine Morphinans Antagonist with agonist properties HO Not orally active Butorphanol N OH 1) Morphinans are more potent and longer acting than their morphine counterparts, but also have higher toxicity and comparable dependence characteristics 2) Changes carried out on morphinans have the same biological effect as those carried out on morphine. Implies the same receptor interactions and binding 3) Simpler molecules and easier to synthesise Morphinans HO A B 6,7-Benzomorphans E Me NMe Me  6,7-Benzomorphans HO HO NMe Me NCH2CH2Ph Me Me Me Metazocine Phenazocine Same activity 4 x activity as morphine of morphine  6,7-Benzomorphans HO HO NMe Pr NMe Pr Me Me Analgesia + Analgesia + suppression of dependence withdrawal symptoms  6,7-Benzomorphans HO Me N Me Pr Me Pentazocine 1/3 analgesic activity (antagonist properties) Short duration Low addiction liability  6,7-Benzomorphans Conclusions 1) Rings C and D are not essential for analgesic activity 2) Analgesia and addictiveness are not necessarily co-existent 3) Clinically useful compounds with reasonable analgesic activity, less addictive liability and tolerance 4) Simpler to synthesise 5) Interact with target binding sites in the same way as morphine 6,7-Benzomorphans REMOVE RING B 4-Phenylpiperidines  4-Phenylpiperidines HO HO A = R E R NMe N Me 67  4-Phenylpiperidines 20% activity of morphine CO2Et Side effects and less sedation Rapid onset and short duration Used in child labour Less likely to affect baby’s breathing N Me Meperidine or pethidine  4-Phenylpiperidines Notes Phenol group is not necessary for activity Ester group is a binding group that is not present in previous structural classes N-Allyl or cyclopropyl groups show no antagonist properties Implies different receptor interactions More flexible molecules may allow different binding modes Very easy to synthesise Meperidine or pethidine 4-Phenylpiperidines Open the piperidine ring E  Methadone Asymmetric centre A A Me * Me = NMe2 Ph Et NMe2 COEt Ph C (R) 2 x activity of morphine O (S) Inactive  Methadone Notes Discovered in Germany during Second World War Useful analgesic and orally active. Slightly sedative Side effects (depresses respiration, dependence potential) Has less severe emetic and constipation effects. Minimal euphoric effect and less severe withdrawal symptoms Used as a substitute for morphine or heroin to treat addicts Flexible molecule - different binding mode from morphine  Rigidification Strategy Less flexible structures More active if active conformation is retained Possibly less side effects Better oral absorption Less easy to make Thebaine MeO O NMe MeO Inactive but useful starting material for the synthesis of rigid opiates (e.g. orvinols)  Synthesis of orvinols (Oripavines) MeO O MeO R O Diels O Alder NMe NMe MeO MeO Thebaine O R MeO HO R’MgBr O O Grignard KOH NMe NMe Ethylene glycol MeO MeO R OH R OH R’ Etorphine (Oripavines) R’ Etorphine (Oripavines) HO O NMe MeO Me OH Pr 10 000 x more active than morphine 20 x affinity for receptor 300 x penetration of BBB Used as a sedative for big game animals Diprenorphine HO O N MeO Me OH Me Antagonist 100 x more active than nalorphine 76  Buprenorphine (1968) HO O N MeO Me OH Me Me Antagonist with agonist properties It is an antagonist at the  and  receptors, and a partial agonist at the  receptor Buprenorphine (1968) Properties (wrt morphine) Clinically useful analgesic No euphoria or addiction liability Low dependence potential Lower respiratory depression Sublingual administration (avoids liver metabolism) Longer duration Side effects (drowsiness, nausea and dizziness) Dissociates slowly from the receptor It is an antagonist at the  and  receptors, and a partial agonist at the  receptor It is 100 times more active than morphine as an agonist. It is 4 times more active than nalorphine as an antagonist. There is a low risk of respiratory depression