Morphinan antagonists

Naltrexone hydrochloride dihydrate (l-7V-cyclopropylmethyl-7,8-dihydro-14-hydroxy-morphinan-6-one hydrochloride) [16676-29-2] M 413.9, m 274-276°, [a] -173° (c 1, H2O), pKEst(i) 6 (N-cyclopropylmethyl), pKEst(i) (phenolic OH). This narcotic antagonist has been purified by recrystn from MeOH and dried air. The free base has m 168-170° after recrystn from Me2CO. [Cone et al. J Pharm Sci 64 618 7975 Gold et al. Med Res Rev 2 211 7952.]... 

Numerous patents have appeared describing derivatives of 5 and 6 as potential PAMOR antagonists. With the exception of 5 and 6, there are no peer-reviewed publications on structure-activity relationships, in vivo activity, or other preclinical data for the new agents. As viewed from the patent literature, introduction of polar substitutents into the morphinan scaffold is the preferred peripheralization strategy. 

The mixture of agonists-antagonists includes derivatives of morphinane (nalorphine, butorphanol), phenanthrene (nalbuphine), derivatives of benzomorphane (pentazocine, dezocine), and derivatives of opipravin (buprenorphine). 

Nagase, H., Endo, T., Kawamura, K., Yamane, S., Suzuki, T., Sato, K. (Toray Industries) Morphinan analogs as ORL1 (opioid orphan) receptor antagonists, JP2000053572 (2000). 

A number of narcotic antagonists based on the morphinan stmcture have been marketed—for example, Buprenorphine, Naloxone, Naltrexone, and Nalorfine. Nalmefene is being pursued for the treatment of alcohol abuse. Oxycodone, and its precursor Codeine, are marketed, with restrictions, as analgesics. noSee Chapter 9, Table 3. 

Again, substitution on the nitrogen with a cyclobutylmethyl group on the morphinan scaffold produces mixed agonist-antagonist activity [18]. The resultant compound is known as butorphanol (21 Stadol Fig. 11.11) [56], and this has increased potency when compared to morphine. It is mainly utilized in the form... 

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. 

Naloxonazine] (morphinan isoquinoline) Synthetic (cl. Morphine) xO-R antagonist [inhibits opiate antinociceptive SM relaxation effects]... 

Morphinan-6-one derivatives are usually more active as analgesics or antagonists than their morphinan counterparts, and replacement of oxygen at... 

Several 4-hydroxymorphinan-6-ones bearing a 14-OH function have been made from oxymorphone (108).(1O9) Here there is a marked contrast in the qualitative action observed relative to the actions seen in the 3,14-dihydroxy-morphinans. Whereas, in the latter, high antagonist activities with little agonism occurred, 4-methoxy-14-hydroxy-N-methylmorphinan-6-one (109b), for example, was 6x as potent as morphine in the MHP antinociceptive assay. This activity is 4 x that of the corresponding 3-OH analog. 

Work on the relationship between chemical structure and pharmacological activity of morphinans to 1966 has been reviewed by Hellerbach et al. s) and morphinans with antagonist properties were reviewed in 1973.(158) As is the case for 4,5-epoxymorphinans (Chapter 2) and benzomorphans (Chapter 4), molecular geometry is the major structure-biological activity influence, although the nature of the N-substituent imparts significant qualitative and quantitative variations in morphinan pharmacology. 

The influence of a 14-OH substituent in 4,5-epoxymorphinans is reflected in the morphinan series Antagonist activities in N-CPM, N-CBM, and N-allyl series are increased relative to corresponding 14-H analogs, and they exert relatively weak analgesic actions This applies, regardless of the 14-OH configuration (i e, morphinan or isomorphinan) The introduction of a 6-oxo function into such structures enhances agonist responses... 

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