K-Opioid receptor antagonist

Chlorophenylpyridomorphinan derivatives, (I), effective as k opioid receptor antagonists were prepared by the author (1) in an earlier investigation and used in the treatment of heroin or cocaine addictions. l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, (II), prepared by Lippa (2) was effective as a dopamine-reuptake inhibitor and was used in the treatment of addiction disorders. 

Portoghese PS, Lipkowski AW, Takemori AE (1987) Binaltorphimine and nor-binaltorphi-mine, potent and selective K-opioid receptor antagonists. Life Sci 40 1287-1292... 

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

Fig. 37.4. Spectral map of the 26 opioid agonists and antagonists in 4 receptor binding tests, as described by Table 37.7 [45, 46]. Circles refer to the compounds. Squares represent the binding tests. Areas of circles and squares are proportional to the marginal mean affinities in the table. The lines that join the three poles (DHM, DADLE and EKC) of the map represent axes of contrast between the p-, 8-and K-opioid receptors. The horizontal and vertical components represent 18 and 79%, respectively, of the interaction in the data.

Page D, McClory A, Mischki T, Schmidt R, Butterworth J, St-Onge S, Labarre M, Payza K, Brown W. Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000 10 167-170. 

Arakawa K, Akami T, Okamoto M, Akioka K, Nakai I, Oka T, Nagase H. Immunosuppression by delta opioid receptor antagonist. Transplant Proc 1993 25 738-740. 

Kong H, Raynor K, Yano H et al. Agonists and antagonists bind to different domains of the cloned k opioid receptor. Proc Natl Acad Sci USA 1994 91 8042-8046. 

Opioid antagonists bind to the opioid receptor with high affinity and have low efficacy. The pure antagonists block the effects of opioids at all opioid receptors. However, as previously discussed, the dose required for naloxone blockade of the jx-receptor versus the k-opioid receptor is several times as much. All opioid antagonists will precipitate withdrawal in opioid-dependent patients. 

Opioid receptor binding Nalorphine is a mixed agonist-antagonist with high affinity and low intrinsic action at the p- and K-opioid receptors. 

Racke K, Hering B, Weber I (1990) Effects of different opioid receptor antagonists on the electrically-evoked release of endogenous dopamine from the isolated neural lobe of the rat pituitary gland in vitro. J Neuroendocrinal 2 335-339. 

Another universal antagonist is the naltrexone-derived nalmefene (14). This 6-methylene derivative of naltrexone shows higher k opioid receptor affinity [51, 52], Nalmefene is a potent, orally active opioid antagonist with a... 

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