Skip to main content

Advertisement

Development of novel N-methyl and N-allyl-substituted oxazolomorphinans and their interaction with opioid receptors

Article metrics

Background

The need for opioid analgesics with reduced undesirable side-effects has initiated a vast amount of scientific efforts, which have led to a number of new opioid ligands and significant expansion of knowledge in opioid pharmacology. The development of morphinans anellated with heterocycles gave rise to several potential therapeutic agents and useful pharmacological tools.

Methods

The chemistry involved the design and synthesis of two sets of oxazolomorphinans having the new heteroring anellated to the A-ring of the morphinan backbone. Binding affinities of the newly synthesized compounds at opioid receptors were determined by in vitro competition binding assays using rat brain (μ, δ) and guinea pig brain (κ) membranes and employing [3H]DAMGO (μ), [3H][Ile5,6]deltorphin II (δ) and [3H]U-69,593 (κ) as specific opioid radioligands. The in vitro pharmacological activities were established using [35S]GTPγS functional assays in membranes from Chinese hamster ovary (CHO) cells expressing human opioid receptors.

Results

Binding studies on the newly synthesized N-methyl and N-allyl derivatives to opioid receptors revealed remarkable results for three compounds: the amino-substituted N-methyloxazolomorphinan showed high affinity and selectivity to the μ opioid receptor, while two N-allyloxazolomorphinans were found to interact with high affinity with μ and κ sites and moderate binding towards δ receptors. In ligand-stimulated [35S]GTPγS binding studies, the N-methyl congener acted as a potent and full agonist at the μ receptor. The two N-allyl derivatives showed antagonistic effects at μ and κ receptors.

Conclusions

The design and synthesis of novel oxazolomorphinans led to an interesting alteration in opioid activity by influencing the biological and pharmacological profile of these compounds interacting with μ, δ and κ opioid receptors.

Acknowledgements

Supported by the Hungarian Research Fund (K81701) and the Austrian Science Fund (FWF: P15481 and TRP 19-B18).

Author information

Correspondence to Attila Sipos.

Rights and permissions

This article is published under license to 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.

Reprints and Permissions

About this article

Cite this article

Sipos, A., Girán, L., Berényi, S. et al. Development of novel N-methyl and N-allyl-substituted oxazolomorphinans and their interaction with opioid receptors. BMC Pharmacol 11, A13 (2011) doi:10.1186/1471-2210-11-S2-A13

Download citation

Keywords

  • Opioid Receptor
  • Chinese Hamster Ovary
  • Binding Study
  • Opioid Analgesic
  • Potential Therapeutic Agent