Benzomorphans antagonists

Table II. Analgesic Antagonist Activity (AD50) of Benzomorphan Antagonists...

Table II. Comparison of Pharmacological Effects of Benzomorphan Antagonists Studied in Man...

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

Grauert, M., Bechtel, W. D., Ensinger, H. A., Merz, H., Carter, A. J. Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex, J. Med. Chem. 1997, 40, 2922-2930... 

As with morphine and the benzomorphans, variation of the N-substituent (Chapters 2 and 4) markedly affects opioid pharmacodynamic activity, and (—) 49 (R = OH R = allyl) known as levallorphan or Lorphan is an antagonist several times more potent than nalorphine. Rather than prepare levallorphan by the N-demethylation 49, (R = OH R = Me) and allylation, on a commercial scale 51 (R and R = H) or 51 (R = H R = CH2C6H5) are obtained optically pure.(34) The former may be allylated and cyclized, whereas the latter was cyclized, debenzylated by hydrogenolysis, and finally converted to levallorphan with allyl bromide. 

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. 

A series of unusual amidinium benzomorphans has been described by Strauss et a/.<53 55) where some members of the series exhibit narcotic antagonist properties. Their synthesis involves a meta bridging process of di- and trinitronaphthalenes (116) with a-phenyl N,N-dimethylacetamidine (117) to produce two isomeric benzazocine amidinium nitronates as their a-phenyl-N,N-dimethylacetamidinium salts (AmH+). The benzomorphan 118 is formed in ethanolic solution, whereas the isomeric benzazocine (119) results from reaction in dimethylsulfoxide. 

Few benzomorphans substituted in the piperidine bridge 4- and 5-positions have been reported. 4,6-Dimethyl- and 5,6-dimethylbenzomorphans with both agonist and antagonist N-substituents have been synthesized 119) and the products demonstrated by H-nmr to bear the 4- and 5-methyl substituents in an equatorial conformation on the piperidine chair (193 and 194, respectively.) Traces of the axial epimers were also detected. 

Benzomorphan pharmacodynamics is dictated by molecular geometry. ( )-ll/3-Alkylbenzomorphans are more active analgesics or mixed agonist/antagonists than their ( )-l la-alkyl counterparts, and the levo antipode is very largely responsible for the narcotic properties of both a- and /3-racemates. This is hardly surprising, as a-(-)-8-hydroxy-3-methyl-6,ll-diethyl-benzomorphan has been shown to have a configuration identical to that of (—)-morphine.(179)... 

Benzomorphans bearing antagonist N-substituents<191) show a similar separation of activities. Where antagonist properties are found predominantly within the (-)-isomers, some activity is seen in the (+)-antipodes. However, the level depends very much upon the nature of the N-substituent and the geometry at C-ll. In several series, activity of the (-)-isomer is consistently more than 2x that of the racemate, suggesting antagonism of the analgesic properties of the (-)-isomer by the (+)-isomer. 

Most attempts to design narcotic antagonists based on 4-phenylpiperidine by linking the basic center to groups such as allyl, substituted allyl, and cyclopropyl methyl (CPM) that confer such properties on fused cyclic systems as possessed by morphine and 6,7-benzomorphans have led to agonists that have no power to block opiate receptors examples include TV-allyl derivatives of norpethidine and norprodine (18)34 and the TV-3-chloroallyl reversed ester 19.(56) Essentially similar results were found for a group of TV-substituted... 

Apart from a few notable exceptions (see later), all known narcotic antagonists are based on the morphine, morphinan, or benzomorphan polycyclic systems, that is, on three closely related groups of opioid ligands that share many structure-activity relationships (see Chapters 2, 3, and 4). Details of antagonist representatives of each group will now be given, chiefly confined to N- allyl and N-cyclopropylmethy 1 (CPM) derivatives, with minimal chemical details. 

Table 12.3. Diastereoisomeric Benzomorphan Analgesic-Antagonists (Racemic Mixtures Unless Otherwise Stated) 1...

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