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Delta Opioid Receptor (DOR) Ligands and Pharmacology: Development of Indolo- and Quinolinomorphinan Derivatives Based on the Message-Address Concept

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Delta Opioid Receptor Pharmacology and Therapeutic Applications

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 247))

Abstract

The pharmacology of the delta opioid receptor (DOR) has lagged, mainly due to the lack of an agonist with high potency and selectivity in vivo. The DOR is now receiving increasing attention, and there has been progress in the synthesis of better novel ligands. The discovery of a selective receptor DOR antagonist, naltrindole (NTI), stimulated the design and synthesis of (±)TAN-67, which was designed based on the message-address concept and the accessory site theory. Intensive studies using (±)TAN-67 determined the DOR-mediated various pharmacological effects, such as antinociceptive effects for painful diabetic neuropathy and cardiovascular protective effects. We improved the agonist activity of TAN-67 to afford SN-28, which was modified to KNT-127, a novel compound that improved the blood–brain barrier permeability. In addition, KNT-127 showed higher selectivity for the DOR and had potent agonist activity following systemic administration. Interestingly, KNT-127 produced no convulsive effects, unlike prototype DOR agonists. The KNT-127 type derivatives with a quinolinomorphinan structure are expected to be promising candidates for the development of therapeutic DOR agonists.

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  • 16 July 2019

    The book was inadvertently published with error in the following chapters.

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Acknowledgments

We thank Prof. Tsutomu Suzuki, Prof. Junzo Kamei, Prof. Minoru Narita, (Hoshi University), Prof. Hideaki Fujii (Kitasato University), and Director Mitsuhiko Yamada (National Center of Neurology and Psychiatry) for their continuous support of research on the DOR ligand and its pharmacology.

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Authors and Affiliations

  1. Department of Neuropsychopharmacology, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo, 187-8553, Japan

    Akiyoshi Saitoh

  2. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Hiroshi Nagase

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  1. Akiyoshi Saitoh
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  2. Hiroshi Nagase
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Correspondence to Hiroshi Nagase .

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  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Emily M. Jutkiewicz

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Saitoh, A., Nagase, H. (2016). Delta Opioid Receptor (DOR) Ligands and Pharmacology: Development of Indolo- and Quinolinomorphinan Derivatives Based on the Message-Address Concept. In: Jutkiewicz, E. (eds) Delta Opioid Receptor Pharmacology and Therapeutic Applications. Handbook of Experimental Pharmacology, vol 247. Springer, Cham. https://doi.org/10.1007/164_2016_18

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