MSOP1016 Science of Medicine: Opioid Analgesics Lecture 4&5

Morphine is a narcotic analgesic isolated from opium, with over 20 different alkaloids present. It has a t-shaped molecular structure and contains functional groups capable of forming ionic, hydrogen bonds, and van der Waals interactions.

Morphine was first isolated in 1804, but its correct structure was not proposed until 1952. Morphine interacts with opioid receptors, specifically mu (μ), kappa (κ), and delta (δ) receptors, which are responsible for its analgesic and side effects.

Opioid analgesics, including morphine, are used to manage chronic pain, as an inducing agent, or as an analgesic supplement with general anesthetics. They can also be used as anti-diarrhea and antitussive drugs, or as analogues to counter addiction to more potent opioids.

Morphine has several side effects, including respiratory depression, nausea and vomiting, pupil constriction, constipation, euphoria, itching, tolerance, and dependence.

Heroin, another opiate, is structurally related to morphine but crosses the blood-brain barrier more easily, leading to stronger analgesic effects and more severe side effects.

The structure of morphine plays a significant role in its biological activity through structure-activity relationships (SAR). SAR analysis has shown that the alkene and 6-hydroxy groups are not essential for activity, but the phenolic group is important.

Opioid drug design aims to maintain activity, lower side effects, and increase oral activity. Stereochemistry plays a role in opioid drug design, as the enantiomer levo (-) morphine is biologically active, and the enantiomer dextromorphan has antitussive effects but no analgesic activity.

Drug extension, or the addition of extra functional groups to a lead compound to probe for extra binding regions in a binding site, can increase activity and decrease side effects. For example, the introduction of a C-14 hydroxyl group increases the activity for oxymorphone and oxycodone, while the phenethyl group increases activity by 14-fold.

Morphine is a morphine agonist, N-Phenethylmorphine is a drug with an extended N-atom, which leads to the development of antagonists such as naloxone, naltrexone, and nalorphine.

Morphine antagonists bind to analgesic receptors without activating them, and block morphine from binding.

Nalorphine, an antagonist, has some agonist activity, while Naloxone and Naltrexone are pure antagonists.

Morphine antagonists are useful for treating addiction and morphine overdose.

Morphine and its analogs have different binding modes based on the presence or absence of functional groups.

Simplification of morphine analogs can lead to easier synthesis, changes in activity and side effects.

Removing ring D results in a series of tetracyclic compounds called morphinans, which include simplified morphine (N-methylmorphinan), levorphanol, and levaldolphin.

The introduction of a phenolic hydroxyl group into morphine leads to levorphanol, which is 5 times more potent than morphine.

The application of drug extension strategy results in more potent and longer-acting morphine analogues such as N-phenyllevorphanol and N-methyllevorphanol.

The removal of rings C and D leads to benzomorphans, which retain analgesic activity and have simplified structures.

Replacing the N-methyl group of metazocine with a phenyl group leads to phenazocine, which is 4 times more potent than morphine and has no dependence properties.

The development of benzomorphans led to the creation of pentazocine, which is useful for long-term analgesia with a very low risk of addiction and has hallucinogenic activity.

The removal of rings C and D from morphine leads to benzomorphans, which have the same SAR results as morphinans and suggest binding to a common receptor.

The removal of ring B from morphine leads to 4-phenylpiperidines such as methadone and pethidine, which have less side effects, less sedation, and a rapid onset and short duration.

Morphine analogues, including simplified morphine (N-methylmorphinan), levorphanol, and levaldolphin, are more potent and longer-acting than morphine but also have higher toxicity.

The removal of rings C and D from morphine leads to the creation of benzomorphans, which retain analgesic activity and have simplified structures.

Replacing the N-methyl group of metazocine with a phenyl group leads to phenazocine, which is 4 times more potent than morphine and has no dependence properties.

The development of benzomorphans led to the creation of pentazocine, which is useful for long-term analgesia with a very low risk of addiction and has hallucinogenic activity.

Simplification strategies for morphine and its analogs include removing non-essential functional groups, excess rings, and asymmetric centres.

Simplification can make the synthesis process easier, quicker, and cheaper, but may also result in changes in activity, side effects, and binding properties.

Morphine was discovered during the Second World War and is a powerful analgesic, but it is slightly sedative and has side effects such as respiratory depression, dependence potential, and emetic and constipation effects.

Morphine can be rigidified to create less flexible structures that retain activity and possibly have fewer side effects and better oral absorption.

Buprenorphine, a morphine analogue, was developed in 1968 and is clinically useful as a long-acting analgesic with no euphoria or addiction liability, and it dissociates slowly from the receptor. It has side effects such as drowsiness, nausea, and dizziness, and is an antagonist with agonist properties with low dependence potential and lower respiratory depression.