Naltrexone, structure

Additional options for refractory disorders include the augmentation of antidepressant treatment with an opiate blocking agent such as naltrexone or consideration of partial or full hospitalization to provide a more structured environment for normalizing the aberrant eating behavior. 

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. 

Naltrexone and nalmefene are structurally related to naloxone. Naltrexone is the /V-cyclopropy I methyl analogue of oxymorphone while nalmefene is the /V-allyl analogue. They have similar pharmacological properties to naloxone but with longer durations of action, with elimination half-lives in excess of 8 hours. They also have significant oral availability. They are used mainly in the management of addicts. 

Nalmefene is a pure opioid antagonist, which is structurally similar to naloxone and naltrexone. 

Inim naltrexone - (sec Reduction of Ketone Carbonyls" for structure) are two examples of highly stereosclec-lisc binreduetion processes in humans. 

FIG. 5. The number of errors on an inclined plane response flexibility problem (Thompson et al 1990) is shown for the same groups of animals as seen in Fig. 4. Saline-treated controls made the fewest errors. Animals exposed to the neurotoxin MAM were slower to abandon a previously learned solution to try new routes to food. However, animals treated postnatally with naltrexone, an opiate receptor antagonist reported to induce dendritic arborization and spine formation, showed performance similar to controls. Decreases in neuron number, such as seen with MAM exposure prenatally, have adverse effects on tests of rat intelligence. Treatments that induce dendritic arborization and synapse formation can ameliorate these deficits. The ability to modify brain structure permits direct testing of the causal role of variation in brain structure and behavioural performance. 

Thompson R, Crinella FM, Yu J 1990 Brain mechanisms in problem solving and intelligence a lesion survey of the rat brain. Plenum Press, New York Witelson SF, McCulloch PB 1991 Premortem and postmortem measurement to study structure with function a human brain collection. Schizophr Bull 17 583-591 Zagon IS, McLaughlin PJ 1984 Naltrexone modulates body and brain development in rats a role for endogenous opiod systems in growth. Life Sci 35 2057—2064... 

Naltrexone (1) has a 14-OH group in addition to the 4,5-epoxymorphinan structure, which comprises four sequential asymmetric centers with two OH groups, and a basic nitrogen. This structure has led to many complex intramolecular reactions. In fact, in 1989 and 1990, we showed that the 14-OH group participated in several characteristic intramolecular reactions [13, 14]. 

Figure 1 shows several structures derived from naltrexone (1) with various types of reactions, including bond scission, cyclization, and rearrangements. Some reactions occur due to intramolecular interactions with the 14-OH group. First, we will describe the reactions that involve 14-OH participation, then we will describe other reactions. We will also describe some oligomerization reactions that produce two... 

The 6-keto group of naltrexone (1) is accessible to nucleophilic attack from the [5-side to provide 6ot-alcohol derivatives. Therefore, we attempted to synthesize a 6a-epoxide derivative 24 of naltrexone with a stable sulfur ylide derived from trimethylsulfoxonium iodide [24]. The 6ot-epoxide 24 was expected to convert to the objective oxabicyclo[2.2.2]octane derivative 20. Instead, the 6 3-epoxide 23 was obtained in 67% yield, but not the objective 6ot-epoxide 24 (Scheme 6). The structure of 23 was determined by X-ray crystallographic analysis (Fig. 8). 

We first attempted to dealkylate the CPM group in naltrexone derivative 35 with 1-chloroethyl chloroformate (ACE-C1) under the original reaction conditions [33] however, the reaction hardly proceeded. After extensive investigation, we found that the piperidine ring of naltrexone derivative 35 could be cleaved with ACE-C1 (9 equiv.) in pyridine to give, surprisingly, oxazolidinone 36 in 60% yield concomitantly with the starting material 35. However, that reaction did not produce the objective carbamate derivative 37 (Scheme 15, condition (a) Fig. 9 shows the structure of compound 37). Therefore, we focused on the abnormal reaction that... 

Fig. 7 Structures of nalbuphine (22), naltrexone (23), naloxone (24), and twin drugs 25-27...

Nahnefene is a newer opioid antagonist that is structurally similar to naltrexone, but with a number of potential pharmacologic advantages for the treatment of alcohol dependence, including no dose-... 

Although the Alza poly(ortho ester) system has never been structurally identified other than by its tradename Chronomer, and later Alzamer, several publications provide a general description of the use of the polymer for the release of naltrexone (46) and contraceptive steroids (47. 48, 49). 

The structural similarity of nalbuphine to naltrexone could not be greater, yet the latter exhibits no analgesia. The reason for this still awaits an explanation. 

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