Methadone, structure

Many methadone derivatives have been prepared with varying degrees of analgesic potency and duration of action. Variations of the methadone structure and some derivatives are shown in scheme 5. 

Synthesis of the intermediate aminonitrile for methadone by (I r giospecific route served to confirm the structure. Alkyla-I Lon of diphenylacetonitrile with l-chloro-2-propanol affords the. ilcohol, 120, free of isomeric products (although it is possible here, too, to imagine cyclization of the halide prior to alkyla-lion). The hydroxyl is then converted to the bromide (121) by... 

Extensive molecular dissection of the morphine molecule over the past several decades led to a host of molecules which showed narcotic analgesic activity even though they possessed but faint suggestion of the structural features present in morphine itself. Thus, both cyclic molecules such as meperidine (70) and alphaprodine (71), and acyclic Compounds such as methadone (72) were found to be effective analgesics. Common features of these compounds were formalized by the Beckett-Casy rule, which states as minimal required structural features (a) an aromatic ring attached to... 

The PE spectra of some other alkaloids like methadone and the opiate narcotics morphine, codeine and heroin have been investigated by Klasinc and coworkers95. Also in this study structure-activity relationships based on IPs were sought but not found. Since the interaction of the drug molecule with the receptor is highly specific, it is not unreasonable that the molecular rather than the electronic structure is more important for the physiological activity. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

A number of novel structures containing a quaternary diphenyl carbon centre, as in methadone, have been described. Certain basic amides (XXXV) of O-ethylbenzilic acid are active by mouth in mice and rats. The most active members are somewhat more potent than pethidine and carry [3-arylethylamino V-substituents such as phenethyl and 2- (or 4-) pyridylethyl. Detailed pharmaco-... 

Morphine was known to the Sumerians and Egyptians as a very valuable pain killer in medicine it is also a powerful narcotic that is habit forming. A great deal of effort has been spent in finding a derivative of morphine that has its good properties, and less of its bad properties. Then, in 1944, demerol and methadone were discovered, which are even more powerful than morphine, but bear no structural relation to morphine. The leading theory now is that both morphine and methadone have the same T-shape, and may fit the receptor. 

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. 

Propoxyphene (dextropropoxyphene Darvon) is structurally related to methadone but is much less potent as an analgesic. Compared with codeine, propoxyphene is approximately half as potent and is indicated for the treatment of mild pain. It is not antipyretic or antiinflammatory like aspirin and is less useful than aspirin in most cases of mild pain. Toxicity from propoxyphene, especially in combination with other sedatives, such as alcohol, has led to a decrease in its use. Death following ingestion of alcohol in combination with propoxyphene can occur rapidly (within 20 minutes to 1 hour). The drug is not indicated for those with histories of suicide or depressive illnesses. 

The MMT is an example of motivational structure connected with the prescription of methadone that has been created by several treatment agencies in the Netherlands. 

Those in this condition were prescribed methadone on a fixed reduction schedule (5 mg reduction every two weeks). Therapy consisted of brief intensive sessions with initial emphasis on engaging the family in the treatment programme. The theoretical approach of our therapy derived from both a structural and strategic model, described earlier. 

Propoxyphene (Schedule II) is another opiate prescribed for pain which is much weaker than those mentioned above. Notice the structural similarities to methadone. Its effects last longer than many other drugs in this class which means it can be taken less frequently and the potential of abuse will be lessened. It can also be formulated with aspirin or acetaminophen in order to have a summation effect. 

The structure of methadone (black) superimposed on that of morphine (blue and black). 

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