Benzomorphan antagonists derivatives

Another structural feature present in 1 and 2 but absent from 3 is a phenethylamine fragment. The absence from this set of a tricyclic derivative coupled with the high clinical interest shown in phenazocine (16) prompted us to turn our attention to the synthesis and pharmacological evaluation of a series of antagonists derived from the benzomorphan nucleus. May and his associates (7, 15) prepared the N-methyl derivatives, 5 and 6, according to the sequence outlined in Figure 1. Demethylation followed by realkylation furnished the desired compounds in both the a (cis) and ft (trans) series. 

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... 

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. 

Neumeyer, J.L., Bidlack, J.M., Zong, R., Bakthavachalam, V., Gao, P., Cohen, D.J., Negus, S.S., Mello, N.K., 1999. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives. Mixed kappa agonists and mu agonists/antagonists as potential pharma-cotherapeutics for cocaine dependence. J. Med. Chem. (in press). 

A group of cycloalkylmethyl derivatives, of which 10 was the prototype, was prepared as indicated in Figure 1. Compound 10 was a potent meperidine antagonist comparable to 9 (R = CH3 R = CH2C = CH2). In contrast to the alkenyl-substituted benzomorphans, the members of the cycloalkylmethyl-substituted series were potent on the inclined screen and showed some degree... 

The benzomorphans thus far studied were all racemic. In view of the diverse pharmacological properties of the cycloalkylmethyl derivatives it was desirable that the compounds be resolved to ascertain wherein each action resided. Fortunately, for comparison with the morphine and morphinan nuclei we had available from Gates (8) the corresponding cyclopropylmethyl derivatives, 13 and 14. Table IV compares the analgesic antagonist activity of a group of cyclopropylmethyl derivatives with the resolved optically active dimethylallylbenzomorphan, 9. 

Those interested in an in-depth understanding of the SAR for p receptor antagonists should be aware that properly substituted N-methyl-4-phenylpiperidines, N-methyl-6,7-benzomorphans, and even nonphenolic opioid derivatives that have good antagonist activity are known. 

Potent and selective k agonists that lack antagonistic properties at any of the opioid receptors are found in a number of frans-1-arylacetamido-2-aminocyclohexane derivatives. There are not enough compounds reported in this class to develop strong trends in SARs. The relative mode of receptor binding for the morphine-related verses the arylacetamide k agonists is not known. Evidence exists for the selective binding of the arylacetamides to ki and of the benzomorphan compounds (e.g., bremazocine) to K2 and ks opioid receptor subtypes. 

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