Oxymorphone-naloxone

Hydrazone derivatives 258 of oxymorphone, naloxone, and naltrexone have been made by reaction with anhydrous hydrazine and designated oxymor-phazone (170), naloxazone (171), and naltrexazone (172). All three hydrazones exhibited a high binding affinity for in vitro rat brain receptor sites. 

A hypothesis has been advanced to explain the different pharmacological response to opioid agonists and antagonists in terms of conformational differences about the basic center, as discussed in Chapter 13. However, a study by 13C-nmr of two such pairs (morphine-nalorphine, oxymorphone-naloxone) revealed little difference between agonist and antagonist molecules in either piperidine ring conformation (chairs only) or ratio of N- R axial to equatorial forms (83 17 for morphine, virtually 100% eq JV-R for 14-OH derivatives).035 ... 

Naltrexone Naltrexone, (-)-17-(cyclopropyhnethyl)-4,5-epoxy-3,14-dihydroxymorphi-nan-6-one (3.1.93), is an iV-cyclopropylmethyl derivative of oxymorphone (3.1.82). One of the methods of synthesis is analogous to the synthesis of naloxone, which consists of using cyclopropyhnethylbromide instead of allylbromide [59]. 

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. 

Figure 7.7 Chemical structure of naloxone and oxymorphone. Note how the small difference in structure changes the full agonist, oxymorphone, into the antagonist, naloxone. and alvimopan, with activity that is restricted to peripheral receptors.

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

Buccal delivery of opioid analgesics and antagonists can improve bioavailability relative to the oral route. Esterification of the 3-pheno-lic hydroxyl group in opioid analgesics such as nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan improved bioavailability and eliminated the bitter taste. The prodrug of morphine,... 

Nalbuphine is structurally related to both naloxone and oxymorphone. It is an agonist-antagonist opioid possessing a spectrum of effects that resemble those of pentazocine however, nalbuphine is a more potent antagonist at p receptors and is less likely to produce dysphoria than is pentazocine. 

EN 1639A UM 792 Nalorex " Trexan ) is one of the phenanthrene series and an analogue of oxymorphone and thebaine, and is also an analogue of the antagonist naloxone. It is a (largely subtype-unselective) opioid RECEPTOR antagonist, and is used orally in detoxification treatment for formerly opioid-dependent individuals to help prevent relapse. 

Among opioids, morphinans (Fig. 1) play an important role as therapeutically valuable drugs. Representative examples of the morphinan class of compounds (Fig. 2) are p-opioid analgesic agents for the treatment of moderate-to-severe pain such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogs (e.g. levorphanol, butorphanol) [19-21], Codeine is also an effective antitussive drug. The oxymorphone derivatives naloxone [22] and naltrexone [23] represent... 

Iorio MA, Frigni V (1984) Narcotic agonist/antagonist properties of quaternary diastereo-isomers derived from oxymorphone and naloxone. Eur J Med Chem 19 301-303... 

The 17 - N- a 11 y I - (n a I o x o n e. 3a) and 17 - /V-c v c lop I opv I m e t h v I (naltrexone, 3b) analogues of oxymorphone (2d) are the prototype opioid receptor antagonists with some selectivity for MOR. They have entered clinical practice as treatments for narcotic overdose (naloxone) and alcoholism or opioid abuse/dependence (naltrexone). The 17-quatemary derivative of naltrexone, methylnaltrexone (4) has recently been introduced into clinical practice as a treatment for opiate-induced bowel dysfunction [1],... 

The 17-substituent of morphinans is believed to influence its agonistic or antagonistic activity towards the opioid receptor [5]. For example, 17-methyl morphinans, morphine, and oxymorphone are agonists. On the other hand, 17-aflyl and 17-cyclopropylmethyl (CPM) morphinans, naloxone and naltrexone (1) are antagonists [5]. Therefore, a dealkylation, especially demethylation reaction of 17-substituents has been widely used to synthesize morphinan derivatives that possess various 17-substituents [27-33]. However, the reaction with chloroformates has only been applied to 14-H-morphinans. Therefore, we were interested in the 17-dealkylation reaction in 14-OH-morphinans, like naltrexone (1). In the course of the study, we found a novel reaction that cleaved the C16-N17 bond in a naltrexone derivative 35 that produced oxazolidinone 36, which lacked a D-ring (Scheme 15). 

H proton, and an eq-NMe/ax-NMe ratio of about 5 is found for morphine and nalorphine salts based on integration of major and minor 9-H resonanees. The eq-NMe epimer is more favoured in oxymorphone and naloxone (ratio near... 

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