title: Opioids in preclinical and clinical trials.
abstract: Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues established types of opioid receptors (these are now classified into mu, delta, and kappa types). Later, Portoghese discovered a highly selective mu type opioid receptor antagonist, beta-funaltrexamine. This led to the finding that the mu type opioid receptor was correlated to drug dependence. Consequently, delta, and particularly kappa, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 and TRK-820 (nalfurafine hydrochloride).
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D008969:Molecular Sequence Data; D009019:Morphinans / Q000494:pharmacology* / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: C532661:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo(3,2,1-ij)quinolino(2',1'-6,7)morphinan-3,14-diol; D000996:Antitussive Agents; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D009271:Naltrexone