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Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions

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Chemistry of Opioids

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 299))

Abstract

Among opioids, morphinans play an important role as therapeutically valuable drugs. They include pain relieving agents such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogs (e.g. levorphanol). Currently used opioid analgesics also share a number of severe side effects, limiting their clinical usefulness. The antagonist morphinans, naloxone and naltrexone are used to treat opioid overdose, opioid dependence, and alcoholism. All these opioid drugs produce their biological actions through three receptor types, µ, δ, and κ, belonging to the G-protein-coupled receptor family. Considerable effort has been put forward to understand the appropriate use of opioid analgesics, while medicinal chemistry and opioid pharmacology have been continuously engaged in the search for safer, more efficacious and nonaddicting opioid compounds, with the final goal to reduce complications and to improve patient compliance. Toward this goal, recent advances in chemistry, ligand-based structure activity relationships and pharmacology of 14-alkoxymorphinans are reviewed in this chapter. Current developments of different structural patterns of 14-alkoxymorphinans as research tools and their potential therapeutic opportunities are also summarized.

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Abbreviations

[35S]GTPγS:

Guanosine-5′-O-(3-[35S]thio)-triphosphate

AD50 :

Analgesic dose necessary to elicit a 50% effect

BBB:

Blood–brain barrier

CBE:

Colonic bead expulsion test

CHO:

Chinese hamster ovary

CNS:

Central nervous system

DMF:

N,N-dimethylformamide

ED50 :

Effective dose necessary to elicit a 50% effect

GPI:

Guinea pig ileum bioassay

HP:

Hot-plate test

IC50 :

Concentration necessary to produce a 50% effect

IL-2:

Interleukin-2

K i :

Inhibition constant

MeOH:

Methanol

MLR:

Mixed lymphocyte reaction

MVD:

Mouse vas deferens bioassay

NaH:

Sodium hydride

NTB:

Naltriben

NTI:

Naltrindole

PBMC:

Peripheral blood mononuclear cells

PPOM:

14-Phenylpropoxymetopon

PPQ:

Paraphenylquinone writhing test

RVD:

Rat vas deferens bioassay

SAR:

Structure–activity relationship

s.c.:

Subcutaneous

TF:

Tail-flick test

TosMIC:

Tosylmethylisocyanid

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Acknowledgments

This work was supported by grants from the Austrian Science Fund (P11382, P12668, P15481, and P21350), European community (EPILA, QLK6-1999-02334), National Institute on Drug Abuse (N01DA-1-8816), and Drug Evaluation Committee of the College on Problems of Drug Dependence of the USA (N01DA-1-7725).

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  1. Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52a, 6020, Innsbruck, Austria

    Helmut Schmidhammer & Mariana Spetea

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  1. Helmut Schmidhammer
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  2. Mariana Spetea
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Correspondence to Helmut Schmidhammer .

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  1. School of Pharmaceutical Sciences, Dept. Medicinal Chemistry, Kitasato University, Sirokane 5-9-1, Tokyo, 108-8641, Japan

    Hiroshi Nagase

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Schmidhammer, H., Spetea, M. (2010). Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions. In: Nagase, H. (eds) Chemistry of Opioids. Topics in Current Chemistry, vol 299. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2010_77

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