Benzomorphans peptides

In addition to the opioid peptides which occur in the mammalian brain, it is now evident that morphine, codeine and related benzomorphans occur naturally, in trace amounts, in the brain, where they exist in a conjugated form usually bound to brain proteins. The significance of these substances to brain function is unclear. 

The fact that N-arginyl-Met-enkephalin(/3-lipotropin 60-65) has an activity comparable with that of the parent by in vitro tests,<173) prompted the examination of benzomorphan derivatives in which the piperidino nitrogen was linked to a variety of amino acids (Gly, Met, Leu, Arg). The Arg derivative 20 was close in potency to Met-enkephalin in a binding assay against [3H]naloxone (as was the nor-base) and all others had very low activities.074 Peptidase action, liberating the active drug from Arg derivatives of both the enkephalin and benzomorphan, may explain these results, although there is contrary evidence in the case of peptide. 

Ten years ago, when this project began in the Parke-Davis Laboratories there were a number of chemical structures reported in the literature as possessing high affinity for the kappa opioid receptor. Some of these are shown below (fig. 1). They include the endogenous peptide, dynorphin, the benzomorphan derivative EKC, the benzodiazepine tifluadom, and the 1,2 aminoamide U-50488. 

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