S opioid receptor antagonists

Kamei, J., Iwamaoto, Y., Suzuki, T., et al. Involvement of 8-,-opioid receptor antagonism in the antitussive effect of S-opioid receptor antagonists, Eur. J. Pharmacol. 1994, 257, 291-294. 

Rational Drug Design of S Opioid Receptor Agonist TAN-67 from S Opioid Receptor Antagonist NTI... 

Portoghese PS, Sultana M, Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide S-opioid receptor antagonist. Eur J Pharmacol 146 185-186... 

Nagase H, Fuji H (2007) Rational Drug Design of S Opioid Receptor Agonist TAN-67 from S Opioid Receptor Antagonist NTl. 8 99-125 Nagata T, see Nishida A (2006) 5 255-280 Nahas NM, see El Ashry ESH (2007) 7 1-30... 

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. 

Portoghese, P.S., Sultana, M., Nagase, H., Takemori, A.E. Application of the message-address concept in the design of highly potent and selective non-peptide 8 opioid receptor antagonists, J. Med. Chem. 1988, 31, 281-282. 

In 1951, disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence other than detoxification. Disulfiram inhibits a key enzyme, aldehyde dehydrogenase, involved in breakdown of ethyl alcohol. After drinking, the alcohol-disulfiram reaction produces excess blood levels of acetaldehyde, which is toxic in that it produces facial flushing, tachycardia, hypotension, nausea and vomiting, and physical discomfort. Opioid receptors antagonists, such as naloxone and naltrexone (see Chapter 47) that block opioid receptors have been found to decrease alcohol consumption (Cornish et al 2004). 

A series of cyclic conformationally constrained peptides related to somatostatin were designed, synthesized and tested for opioid receptor interaction by Hruby and his collaborators. Compounds (17)-(22) were found to be pure opioid antagonists (GPI) with high affinity (IC50 = 1.2 to 4.3 nM) and exceptional selectivity for p over S opioid receptors (Table 3.1) and with minimal or no somatostatin-like activity (ligand binding assays)[63-65]. 

The enantiomerically pure diarylmethylpiperzine derivative, (-)-3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-l-piperazinyl)-(3-thienyl)-methyl)phenol, (VI), prepared by Chang (5) was effective as an opioid receptor antagonist and used as a therapeutic agent in treating drug and alcohol addictions. 

The concept of bridging has also been applied to antagonists bivalent ligands containing /3-naltrexamine pharmacophores (p. 67) linked by an oligoethylene glycol spanner have been described that differentially block /x, k, and S-opioid receptors.(198) Thus, 10a (with a six-ethylene-units spanner) most effectively blocks S-receptors (DADL on MVD), while 10b (with shorter spanner) acts preferentially at k-sites (ethylketazocine on GPI). 

Arakawa K, Akami T, Okamoto M, Nakajima H, Mitsuo M, Nakai I, Oka T, Nagase H, Matsumoto S (1992) Immunosuppressive effects of 5-opioid receptor antagonist on xenogeneic mixed lymphocyte response. Transplant Proc 24 696-697... 

McLaughlin JP, Sebastian A, Archer S, Bidlack JM (1997) 14 Beta-chlorocinnamoylamino derivatives of metopon long-term mu-opioid receptor antagonists. Eur J Pharmacol 320 121-129... 

Portoghese, P. S. Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol. Sci. 1989,10, 230-235. 

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