Opioid anagesics are well known for their ability to reduce the perception of pain without a loss of consciousness. The original opioids were derived from opium, which is a partially dried latex harvested fromt the opium poppy, papaver somniferum. Opium contains morphine, codeine, noscapine, papaverine, and thebaine. Thebaine is a convulsant drug that produces no analgesia, and as such it is not used clinically. However, it is an important synthetic intermediate in the production of semisynthetic opioids. Opium is a less effective analgesic than pure morphine, because it is slowly absorbed, and has been historically used for its constipating action (paregoric). Morphine itself, which was discovered in 1809, has a variety of effects, among which are an increase in the tolerance to pain, somnolence, euphoria, an antitussive effect, respiratory depression, constipation and emesis. In addition, morphine has a high addiction liability. Derivatives of morphine have been sought that retain the anagesic activity of the parent, but that have improved oral bioavailability and a reduction in addiction liability and other deleterious side effects.
The structure of morphine is shown below. The rings are lettered A (aromatic), B (cyclohexane), C (cyclohexene), D (piperidine) and E (tetrahydrofuran). All of the derivatives of morphine which possess this basic ring structure have a high addiction liability which is proportional to their analgesic activity.
The oripavine derivative etorphine is a representative of a particularly potent class of morphine analogues. Etorphine is approximately 1000 times as potent as morphine, and arguably is too potent to be released for human therapy. It is currently used as a tranquilizer for large animals.
There are two agents in the morphine class which are marketed as morphine antagonists. These agents, naloxone and naltrexone, are shown below. Naloxone is a pure antagonist, and is commonly used to treat narcotic overdose. Naltrexone is a similar agent, but does possess weak agonist activity, and is used to treat former narcotic addicts.
The morphinans, which were first intruduced by Grewe in 1946, are similar in structure to the morphine analogues, but lack the E ring found in the naturally occurring opioids, as well as the 6-OH and the 7,8-double bond. Their general structure is represented by levorphanol, which is shown below.
The benzomorphans, which were first introduced by May in 1960, are also similar in structure to the morphine analogues, but lack the C and E rings found in the naturally occurring opioids. Their general structure is shown below.
The representitive 4-phenylpiperidine, meperidine (Demerol, below) was first prepared as an antispasmodic, and in addition to this activity it was found to be analgesic at about 20% the potency of morphine. Note that the compound follows the morphine rule.
In addition to the 4-phenylpiperadines shown above, the opiate analgesic fentanyl, which strictly speaking does not follow the morphine rule, was marketed as a short acting analgesic. Fentanyl, which is 100 times as potent as morphine, is often used for surgical procedures such as endoscopy or colonoscopy.
Open chain analogues which follow the morphine rule can also have significant analgesic activity. The general structure of these analogues appears below:
Methadone accumulates in lipid tissue outside of the CNS, and thus has a slow onset and long duration (24 hours). It is used for long term maintenence of addiction. Propoxyphene is a mild analgesic with a low addiction liability.
As shown above, the opioid receptor is thought to have three main binding areas. There is an anionic site (8 by 6.5 angstroms) that bonds to the charged nitrogen of morphine, a cavity which accomodates the piperidine ring, and a flat surface for binding the aromatic portion of the molecule. All active agonists and antagonists must fit this receptor to some degree. There appear to be four receptor subtypes, termed mu (the morphine receptor), sigma (the phencyclidine receptor), kappa (the ketocyclazocine receptor) and delta (the endorphin/enkephalin receptor).
Endorphins and enkephalins are derived from a 91 amino acid pituitary hormone called beta-lipotropin. On release it is cleaved to form three major active products: residue 61-65 is called met-enkephalin, residue 61-77 is called gamma-endorphin, and residue 61-91 is called beta-endorphin. Beta-endorphin is most active, and is about 20 times as potent as morphine. It can produce dependence and tolerance.
The ergot alkaloids are a group of indole-containing alkaloids that are produced by the mold Claviceps purpurea, a common mold that grows on grains, especially rye. The use of moldy rye in the Middle Ages was responsible for a disease known as St. Anthony's Fire (ergotism), which was characterized by gangrene of the limbs and hallucinations. The cause of the disease was actually due to the lack of blood flow inh the extremities caused by the powerful a-agonist effects of the ergot alkaloids, and their associated CNS stimulatory effects. The structures of some common ergot alkaloids are shown below:
In actuality, crude ergot extract produces a variety of effects, including a-stimulation, a-blockade, CNS stimulation and oxytocic effects. All of the active ergot alkaloids are amides derived from lysergic acid. The best known of these is the powerful hallucinogenic lysergic acid diethylamide (LSD), which produces profound hallucinations through stimulation of the central serotonergic system. Ergotamine is a mixed a-agonist/antagonist at central and peripheral adrenoreceptors, and is also a powerful uterine stimulant. Because it is an effective vasoconstrictor, it is used to limit postpartum bleeding, and can also be used to treat migraine headaches. It can be given orally in combination with caffiene (Cafergot®), which potentiates the vasoconstrictive effect. Other more widely used ergot alkaloids used for migraine are ergonovine (Ergotrate®), methylergonovine (Methergine®) and methysergide (Sansert®). In partucular, methysergide has a lower incidence of uterine stimulatory side effects, and thus is more widely used for migraine.
Interestingly, saturation of the 9,10-double bond of ergotamine derivatives afford analogues which are a-blockers, and thus act as vasodilators. Three such synthetic derivatives, dihydroergocristine, dihydroergocryptine and dihydroergocornine are marketed in combination as their mesylate salts (ergoloid mesylates, Hydergine®). This preparation is used primarily for peripheral vascular disease.
Other Drugs Used for Pain
In a previous module we discussed the used of aspirin, acetaminophen and the NSAIDS for pain. The reader is invited to review these lectures on the PHA 4110 site at wiz2.pharm.wayne.edu/module/pha413.html.
The triptans, shown above, are selective 5-HT1 agonists that are used for the treatment of acute migraine. The hypothesis for their action states that serotonin is a mediator in the development of migraine headache. It is thought that triptans either cause constriction of intracranial blood vessels leading to reduction in pressure, or that they may block the release of proinflammatory neuropeptides from presynaptic nerve terminals. Triptans are used for acute migraine, but not for prophylaxis.
Return to the PHA 4220 Main Page