Antagonists opioid benzomorphan derivatives

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). 

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. 

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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