Opioid Analgesics and Opiates History

• Opioid analgesics are discussed

History of Opium

• Opiates are narcotic analgesics structurally related to morphine
• Opioids are synthetic, semi-synthetic, natural, and endogenous compounds interacting with opioid receptors
• The first opioids were extracted from opium, the sticky exudate of the opium poppy
• Poppy pods are scored, emitting a latex that is scrapped off and dried
• Opium poppies are primarily grown and cultivated in the Mediterranean region
• Opium has been actively collected since ~3400 BC
• Opium is one of the oldest medicines used as a sedative and to treat diarrhea
• In the 18th century, laudanum was popular in Europe and represents an early example of a drug used recreationally
• Opium is highly addictive
• Opium was also smoked in opium dens, widespread globally

Morphine

• Opium contains over 20 alkaloids
• Morphine is the alkaloid responsible for sedative and analgesic activity
• Morphine was first isolated in 1803
• Morphine wasn't used orally until the hypodermic syringe was invented in 1853
• Direct injection of Morphine into the bloodstream revealed it as a more potent analgesic and sedative
• Side effects of Morphine are addiction, tolerance, and respiratory depression
• In 1925, Sir Robert Robinson proposed the correct structure of morphine

Morphine Structure

• The full synthesis of morphine was not achieved until 1952
• Morphine structure was not officially proven until 1968
• Morphine contains five rings (A-E) and a T shape
• Morphine is basic due to the tertiary amino group
• Morphine contains a phenol, alcohol, aromatic ring, ether bridge, and alkene double bond

SAR (Structure-Activity Relationship)

• Multiple morphine analogs have been made to discover SAR
• Alkene and 6-hydroxyl groups can be removed or modified without loss of analgesic properties
• Removal of phenolic groups (codeine, dihydrocodeine, and 3-ethylmorphine) shows a significant drop in analgesic properties
• The phenol OH group, aromatic ring, and tertiary amine are important for analgesic activity
• When synthesized as a racemic mixture, morphine showed a 50% decrease in activity
• The unnatural enantiomer of morphine had no analgesic activity
• Morphine activity depends on functional groups' presence and relative positions (pharmacophore)
• The active site of the target is asymmetrical, accepting only the correct conformation

Target Receptors

• Morphine activates analgesic receptors in the CNS and reduces pain signal transmission to the brain
• Three main opioid receptor types have been identified: mu (μ), kappa (κ), and delta (δ)
• Different opioid receptor types have different effects
• Mu (μ) receptors provide the strongest analgesic effect but also the most severe side effects
• Kappa (κ) and delta (δ) receptors show less analgesia and fewer side effects
• Kappa (κ) receptors are considered the safest, but research has revealed psychological side effects like depression, anxiety, and psychosis

Pharmacodynamics

• Pharmacodynamics describes how a drug binds to its target and produces a pharmacological effect

Functional Binding Groups in Morphine

• Amine nitrogen is protonated and charged, interacting through an ionic bond with a negatively charged region
• The phenol acts as a hydrogen bond donor (HBD) to a hydrogen bond acceptor (HBA)
• The aromatic ring is positioned to allow van der Waals interactions with a hydrophobic region

Pharmacokinetics

• Pharmacokinetics describes how a drug reaches its target and survives metabolism in the body
• Morphine is relatively polar and not well absorbed through the gut
• Morphine is usually administered through IV injection
• Morphine does not readily pass the BBB due to polarity
• A small percentage of morphine enters the CNS and reaches the analgesic receptors
• As a free base, morphine can pass the BBB more readily, then ionize to interact with the receptor
• Increased polarity prevents analogs from crossing the BBB and limits activity
• Prodrugs can mask polarity, allowing drugs to pass the BBB and enter the CNS
• 6-acetylmorphine is 4X more active than morphine
• less polar analog can cross the BBB in greater concentrations
• Morphine has a free phenolic group to interact with the binding group immediately
• Diamorphine (heroin) with two of the polar groups masked is about 2X more active than morphine
• Has acetyl on the phenol removed (by esterases) to bind.
• 6-acetylmorphine is a more potent analgesic with severe tolerance and dependence characteristics

Morphine in the Bloodstream

• Morphine has a short lifetime in the bloodstream
• 90% of the morphine dose is metabolized and secreted within 24 hours
• Alcohol and phenol groups mean that morphine readily undergoes phase II conjugated reactions and is quickly excreted

Analogues: Addressing Morphine's Problems

• Novel orally available Morphine analogues are needed to retain analgesic properties but with fewer side effects
• Drug extension involves adding extra functional groups to a lead compound for probing binding regions
• Two methods showed increased activity in making morphine analogues
• Oxymorphine and oxycodone show increased activity, suggesting an additional hydrogen bond interaction
• Alternating alkyl groups on the nitrogen seem to decrease activity
• Phenethyl groups show 14x in activity over morphine, suggesting a hydrophobic interaction with the aromatic ring

Analogues - More Extension

• If the alkyl group added to the nitrogen are a cyclopropylmethyl or an allyl group analogs act as antagonists of the analgesic receptors and block morphine
• Addition blocks the side effects of morphine and allows use on patients suffering an overdose
• Can be used in addiction therapy by blocking addicts' ability to abuse morphine

Analogues - Simplification

• Simplification of a structure consists of removing parts of the carbon skeleton, chirality, and/or functional groups
• Simplification can make analogs easier to synthesize and may increase activity
• Morphine has five rings and five chiral centers

Analogues - Effects of Ring Removal

• Removal of ring E causes a complete loss of activity, emphasizing the importance of the basic nitrogen
• Removal of the D ring produces analogs that still maintain activity (morphinans)
• Levorphanol is 5X more active but side effects are also increased
• Levorphanol can be taken orally and lasts longer in the body
• Morphinan analogs show similar trends in SAR as morphine
• morphinan analogs are easier to synthesize than morphine

Analogues - Ring Simplification

• Removing rings C and D creates benzomorphans
• Benzomorphans retain analgesic activity, so those rings are not essential
• The same chemical modifications used for morphines also produce similar activity increases and decreases
• Adding a phenylethyl group replacing the N-methyl group resulted in 4X increased activity without dependence properties
• Bremazocine shows 200X activity, a longer duration, and a low risk of addiction
• Bremazocine does not depress breathing but activates the kappa receptor for a psychotomimetic effect
• Analgesia and addiction are not necessarily coexistent
• Removing rings B, C, and D creates the 4-phenylpiperidines
• Pethidine (meperidine) is a is weaker analgesic than morphine, with similar side effects, but rapid onset and shorter duration
• A 4-phenylpiperidine can be used as an analgesic in childbirth
• 4-phenylpiperidines appear to bind differently than previous morphine structural classes because they do not follow the same SAR trends

4-phenylpiperidines

• Agonist of the μ receptor
• Very lipophilic/can easily cross the BBB
• 4-anilinopiperidines are a subclass that includes fentanyl
• Removing rings B, C, D, and E produces methadone
• Methadone was discovered in WWII in Germany and has similar activity to morphine
• methadone has is orally active and has has less severe emetic and constipation effects
• Methadone is often given to drug addicts to wean them off opioids, swapping one addiction for a less dangerous one
• Removing rings B, C, D, and E also produces loperamide
• Loperamide acts as a selective agonist on opioid receptors in the GI tract
• Loperamide is lipophilic, slowly absorbed, and prone to metabolism, so it cannot cross the BBB
• Loperamide is used as an antidiarrheal agent, marketed as Imodium

Analogues - Rigidification Defined

• Rigidification limits the number of conformations to lock the molecule into the correct conformation
• Rigidification should increase activity, improve selectivity, and decrease side effects
• Orvinols (oripavines) exemplify rigidification in the analgesic field
• Etorphine is 10,000X more potent than morphine
• Etorphine has high hydrophobicity (allowing it to cross the BBB 300X more easily)
• It has 20X increased affinity to the analgesic receptor
• It has a considerable margin of safety and is used to immobilize large animals (elephants)
• The high potency of Etorphine means that only small doses are needed and it can be dissolved in small volumes
• This allows it to be placed in darts and be fired into animals

Etorphine Continued

• Reducing the double bond of etorphine increases activity by 10X, which is called dihydroetorphine
• The phenethyl substituent on dihydroetorphine also increases the activity
• These are agonists of the µ receptor and carry the undesired side effects
• Adding a cyclopropyl group to morphine yields diprenorphine
• Diprenorphine is a very powerful antagonist that can be used to reverse the immobilizing effects of etorphine

Agonists versus Antagonists

• Agonists vs antagonists of morphine analogs are an interesting example of compounds binding sites in active versus inactive confirmation
• Adding smaller hydrophobic groups to the short chain on the amine group can result in binding a hydrophobic site in the inactive form of the receptor and stopping signaling
• Larger groups bind a larger hydrophobic region in the active form of the active site