Asim, Muhammad F

Fink, Monika

Follia, Valeria

Garczarczyk, Dorota

Guerrieri, Elena

Rief, Silvia B

Schmidhammer, Helmut

Spetea, Mariana

BMC Pharmacology

English

PubMed

Elena Guerrieri

Valeria Follia

Dorota Garczarczyk

Silvia B Rief

Monika Fink

Muhammad F Asim

Mariana Spetea

Helmut Schmidhammer

Springer - Publisher Connector

MEETING ABSTRACT Open Access
Biological, pharmacological and immunological
activities of novel 6-amino-acid-substituted
14-alkoxy-N-methylmorphinans
Elena Guerrieri, Valeria Follia, Dorota Garczarczyk, Silvia B Rief, Monika Fink, Muhammad F Asim, Mariana Spetea,
Helmut Schmidhammer*
From 17th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint meeting with the
Hungarian Society of Experimental and Clinical Pharmacology (MFT)
Innsbruck, Austria. 29-30 September 2011
Background
Of the three opioid receptors, μ (MOP), δ (DOP) and 
(KOP), the MOP type is the most involved in the action
of opioids in the gut. Experimental studies on models of
intestinal inflammation and inflammatory bowel disease
(IBD) support an anti-inflammatory role of peripheral
MOP receptors in the gut, besides their involvement in
pain control (analgesia) and gastrointestinal motility
(anti-diarrheal effects). Research focuses increasingly on
exploring the therapeutic potential of peripheral MOP
receptors aiming for identification of peripheral ligands
as improved treatment for debilitating conditions asso-
ciated with bowel functions. One strategy to increase
peripheral selectivity includes chemical modifications
that enhance hydrophilicity [1,2]. Our work in the field of
peripherally acting opioids has led to a series of opioids
with zwitterionic moieties (i.e. amino acid residues)
attached to the C-6 position of 14-O-methyloxymor-
phone, which may represent novel therapeutic molecules
for IBD. These 14-alkoxymorphinans were pharmacologi-
cally and immunologically characterized.
Methods
Synthesis of novel zwitterionic 14-alkoxymorphinans
was accomplished by multi-step syntheses. Binding,
functional and immunomodulatory activities were deter-
mined in vitro. Antinociceptive activities were assessed
using acetic acid-induced writhing and tail-flick tests.
Physicochemical properties (logP and logD) were deter-
mined using the MarvinSketch software.
Results
In vitro, the new 6-amino-acid-substituted 14-alkoxymor-
phinans bound with high affinity and showed agonist
activity towards the MOP receptor. They significantly
inhibited the nuclear transcription factor kappaB (NF-
B) activation in tumor-necrosis factor-a (TNF-a) and
lipopolysaccharide (LPS)-stimulated human monocytic
THP-1 cells. In vivo, they produced dose-dependent anti-
nociceptive effects in mice after subcutaneous adminis-
tration, being several-fold more potent than morphine.
Based on the calculated logP and logD values, an increase
of hydrophilicity, and thus peripheral selectivity can be
achieved by attachment of amino acid residues to the
morphinan skeleton.
Conclusions
Novel MOP agonists acting in the periphery with com-
bined immunosuppressive and analgesic properties may
provide a new approach for the treatment of IBD.
Acknowledgements
Supported by the Austrian Science Fund (FWF: P21350 and TRP 19-B18) and
Tyrolean Research Fund (TWF-UNI-0404/949).
Published: 5 September 2011
References
1. Schmidhammer H, Spetea M: Synthesis of 14-alkoxymorphinan
derivatives and their pharmacological actions. Top Curr Chem 2011,
299:63-91.
2. Spetea M, Windisch P, Guo Y, Bileviciute-Ljungar I, Schütz J, Asim MF,
Riba P, Kiraly K, Fürst S, Al-Khrasani M, Schmidhammer H: Synthesis and
* Correspondence: helmut.schmidhammer@uibk.ac.at
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center
for Molecular Biosciences, University of Innsbruck, 6020 Innsbruck, Austria
Guerrieri et al. BMC Pharmacology 2011, 11(Suppl 2):A5
http://www.biomedcentral.com/1471-2210/11/S2/A5
© 2011 Guerrieri et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
pharmacological activities of 6-glycine substituted 14-
phenylpropoxymorphinans, a novel class of opioids with high opioid
receptor affinities and antinociceptive potencies. J Med Chem 2011,
54:980-988.
doi:10.1186/1471-2210-11-S2-A5
Cite this article as: Guerrieri et al.: Biological, pharmacological and
immunological activities of novel 6-amino-acid-substituted 14-alkoxy-N-
methylmorphinans. BMC Pharmacology 2011 11(Suppl 2):A5.
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Biological, pharmacological and immunological activities of novel 6-amino-acid-substituted 14-alkoxy-N-methylmorphinans

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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color ﬁgure charges • Immediate publication on acceptance

Synthesis and * Correspondence: helmut.schmidhammer@uibk.ac.at Department of Pharmaceutical Chemistry, Institute of Pharmacy and

Synthesis of 14-alkoxymorphinan derivatives and their pharmacological actions. Top Curr Chem

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Biological, pharmacological and immunological activities of novel 6-amino-acid-substituted 14-alkoxy-N-methylmorphinans

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