Second generation opioidergic compounds: clinical data

The only second generation opioidergic compound for which there is substantial clinical information is nalmefene. Nalmefene, C21H25NO3, with a molecular weight of 339.43, is a pure opioid antagonist with no abuse potential [1]. Like naltrexone and naloxone, nalmefene was originated by Jack Fishman and co-workers. The three antagonists have rather similar structures and properties. The molecular structure of nalmefene is shown in the Appendix for Chemical Structures. Nalmefene is an analog of naltrexone, while naltrexone is a congener of naloxone. Nalmefene, like naltrexone and naloxone, is a relatively non-specific opioid antagonist, i.e., binding to mu, delta, and kappa opioid receptors. The binding abilities of the three antagonists [2] are shown in Figure 1. Nalmefene is similar to naltrexone in its binding of mu receptors, but somewhat more potent than naltrexone for kappa and delta binding. Both are more potent than naloxone in binding all three opioid receptor types. Thus, naltrexone has been characterized as being relatively selective for mu receptors, whereas nalmefene can be seen as a more universal opioid blocker. There is, however, currently no evidence that these three opioid antagonists differ in their basic actions once they reach the central nervous system.