Morphine synthetic derivatives, opium alkaloids

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

The most widely used agonists in medical practice are the opium alkaloids morphine and codeine. However, semisynthetic derivatives (hydromorphone, oxymorphone, hydrycodon, oxycodone), whose use is even preferred in certain cases, and strong, purely synthetic compounds (methadone, meperidin, fentanyl, sufentanyl, and others) have found wide use. 

The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentaitil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise. 

Buprenorphine is a semi-synthetic derivative of thebaine, one of the opium alkaloids. It is approximately 30 times as potent as morphine. A dose of 0.3 mg intramuscularly has a duration of analgesic action of 6-18 h. Buprenorphine is also effective sublingually. The average bio-availability by this route is about 55%, but absorption is slow and the time to achieve peak plasma concentrations is variable, with a range of 90-360 min. The onset of action is rather slow (5-15 min) after both intramuscular and intravenous administration, possibly due to slow receptor association. Buprenorphine binds to and dissociates from the p receptor very slowly, which may account for its low potential for physical abuse. It also means that buprenorphine-induced respiratory depression is difficult to reverse with naloxone, even with very high doses. Doxapram may in these circumstances be useful. Drowsiness and dizziness are the most common side effects, although they rarely... 

Many opium-derived and other IQs are psychoactive, the best known being the analgesic, addictive, narcotic, opium-derived morphinan alkaloids codeine and morphine (heroin being the semi-synthetic diacetate of morphine). The tertiary or quaternary amine structural component is important for the activity of some Erytkrina alkaloids and bisbenzyliso-quinolines (notably the major curare component (+)-tubocurarine) as antagonists of the nACh-R involved in neuronal excitation of skeletal muscle. The planar disposition of some polycyclic benzophenanthridines enables intercalation (parallel interleaving) between the base pairs of DNA. A variety of naturally occurring and synthetic IQ compounds are protein kinase inhibitors. 

Strychnos usambarensis (Loganiaceae) [root] S. Am. Indian poison curare component Derived synthetically from morphine, a morphinan isoquinoline alkaloid from Papaver somniferum (opium poppy) (Papaveraceae) [aerial]... 

Morphine (21a) was first isolated by Sertumer in 1806, followed by codeine (21b) in 1832 by Robiquet and then the non-morphine alkaloid, papaverine by Merck in 1848, all from crude opium preparations. With the invention of the hypodermic needle and the availability of the purified alkaloids, the benefits and problems associated with these compounds (and their synthetic derivative, heroin) rapidly became apparent, leading to the search for potent dmgs without the abuse potential of the morphinoids. With the exception of the semi-synthetic compound, buprenorphine (22), which is approximately 25-50 times more potent than morphine and has a lower addiction potential, none of the compounds made to date from modifications around the phenanthrene stmcture of morphine have exceeded the pain control properties without a concomitant addiction potential. An interesting compound, whose structure is based on that of morphine is pentazocine (Talwin ) (23). This has about 30% of the efficacy of morphine, but has a much lower incidence of abuse and does in fact cause withdrawal... 

Rice KC (1980) Synthetic opium-alkaloids and derivatives - a short total synthesis of (-1-/—)-dihydrothebainone, (+/—)-dihydrocodeinone, and (-f/—)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners. J Org Chem... 

FIGURE 17.5 Opioids. Morphine and codeine are natural alkaloids in the opium poppy. Heroin is a synthetic derivative with similar activity as a drug, but it is dangerously addictive. 

The opium poppy (Papaver somniferum L. [Papaveraceae]) latex contains benzylisoquinoline alkaloids and is a widely known source of the analgesic drugs morphine and codeine. The biosynthesis of benzylisoquinoline alkaloids begins with a condensation reaction catalyzed by norcoclaurine synthase of DA [161]. The structural features of benzylisoquinoline alkaloids derived from DA might provide some explanation for the documented affinity of some natural alkaloids of this class, and some synthetic derivatives, for DA receptors [162]. Indeed, the chemical structure of morphine has been used as a template for the development of the PD drug, apomorphine (47). Apomorphine includes a catecholaminergic moiety in its... 

Opiates are medications derived from the poppy plant that attach to opioid receptors in the brain. The extraction of morphine from opium marked the beginning of organic alkaloid chemistry and has led to the synthesis of a variety of semisynthetic and synthetic analgesics. Opium and its derivatives have been used for thousands of years not only for pain relief but also for the euphoria that they produce. It is this dual effect that allows them to be so useful but also addictive and therefore dangerous. Understanding their stmcture, action, use, and abuse reflects the close connection that we have with the plant world. 

Opioids are analgesics that work by binding to the opioid receptors found on neurons in various areas of the brain and spinal cord as well as intramural plexuses that regulate the motility of the gastrointestinal and urogenital tracts. Opiates are by definition limited to natural opium alkaloids and their semi-synthetic derivatives. Morphine,... 

Agonists include natural alkaloids of opium (morphine, codeine, and a large blend of natural alkaloids, pantopon, and omnopon), their analogs (hydrocodon and hydromor-phone, oxycodone, and oxymorphone), derivatives of morphinane (levorphanol), and a number of synthetic compounds derivatives of phenylpiperidine (meperidine, promedol), 4-anilidopiperidines (fentanyl, sufentanyl, alfentanil), and derivatives of diphenylheptane (methadone, propoxyphene). 

Opiates are compounds extracted from the milky latex contained in the unripe seed pods of the opium poppy (Papaver somniferum). Opium, morphine, and codeine are the most important opiate alkaloids found in the opium poppy. Opium was used as folk medicine for hundreds, perhaps thousands of years. In the seventeenth century opium smoking led to major addiction problems. In the first decade of the nineteenth century, morphine was isolated from opium. About 20 years later, codeine, one-fifth as strong as morphine, was isolated from both opium and morphine. In 1898, heroin, an extremely potent and addictive derivative of morphine was isolated. The invention of the hypodermic needle during the mid-nineteenth century allowed opiates to be delivered directly into the blood stream, which increases the effects of these drugs. Synthetically produced drugs with morphine-like properties are called opioids. The terms narcotic, opiate, and opioid are frequently used interchangeably. Some common synthetically produced opioids include meperidine (its trade name is Demerol) and methadone, a drug often used to treat heroin addiction. 

A natural product is a compound synthesized by a plant or an animal. Alkaloids are natural products that contain one or more nitrogen heteroatoms and are found in the leaves, bark, roots, or seeds of plants. Examples include caffeine (found in tea leaves, coffee beans, and cola nuts) and nicotine (found in tobacco leaves). Morphine is an alkaloid obtained from opium, the juice derived from a species of poppy. Morphine is 50 times stronger than aspirin as an analgesic, but it is addictive and suppresses respiration. Heroin is a synthetic compound that is made by acetylating morphine (Section 30.3). 

Morphine has an LD50 i.v. in mouse of 226-318 mg/kg (Wink, 1993). Codeine (62) is also an important analgetic and antitussive drug. Codeine is the most widely used morphine type alkaloid it has an LD50 i.p. in mouse of 300 mg/kg (Wink, 1993). This alkaloid is derived from opium (0.2-0.7%) and synthesized by methylation of morphine (Tyler et al, 1981). Heroin (65) (Fig. 32.21), a synthetic diacetate of morphine, crosses the blood-brain barrier more rapidly than morphine and is highly euphoric and analgetic. 

Methadone is a potent synthetic opioid analgesic, structurally unrelated to any of the opium-derived alkaloids. It is a highly lipophilic, basic drug (pKa 9.2) available as a hydrochloride powder formulation that can be reconstituted for oral, rectal, or parenteral administration. Methadone was developed in Germany in 1942 as a synthetic substitute for morphine, and has been approved and widely employed for opioid detoxification maintenance as well as acute and chronic pain management. 

The opiate alkaloids are a mix of semisynthetic and synthetic compounds derived from or related to the extract of the unripe seed pods of the opium poppy Papaver somniferum. Specifically, the alkaloids are obtained from the latex, or milky, exudates of the seed pod that appear when it is cut or sliced. The liquid contains about 10% morphine and about 1.5% codeine, with various amoimts ( 0.2-8%) of papaverine, thebaine, and noscapine (Table 8.3). The... 

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