Opioids in Preclinical and Clinical Trials

  • Hiroshi NagaseEmail author
  • Hideaki Fujii
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 299)


Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, 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 [6] and TRK-820 (nalfurafine hydrochloride) [7].

Graphical Abstract


Clinical development Nonnarcotic Opioid drug TRK-820 TRK-851 



Acetic acid writhing


Absorption, distribution, metabolism, and excretion


Adverse drug reaction




Blood–brain barrier



cLog P

Calculated log P


Central nervous system




[d-Ala2, N-Me-Phe4, Gly-ol5]enkephalin


[d-Pen2, d-Pen5]enkephalin




Guinea pig ileum


High-performance liquid chromatography










Mouse vas deferens






Phosphate-buffered saline




Structure–activity relationship




Standard error of the mean


Tail flick


Visual analog scale


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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.School of PharmacyKitasato UniversityTokyoJapan

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