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

MEETING ABSTRACT Open Access Development of novel N-methyl and N-allylsubstituted oxazolomorphinans and their interaction with opioid receptors Attila Sipos 1,2* , Levente Girán 1 , Sándor Berényi 1 , Sándor Antus 1 , Helmut Schmidhammer 2 , Mariana Spetea 2 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 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)andguineapigbrain () membranes and employing [ 3 H]DAMGO (μ), [ 3 H] [Ile 5,6 ]deltorphin II (δ)and[ 3 H]U-69,593 () as specific opioid radioligands. The in vitro pharmacological activities were established using [ 35 S]GTPgS 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 aminosubstituted N-methyloxazolomorphinan showed high affinity and selectivity to the μopioid receptor, while two N-allyloxazolomorphinans were found to interact with high affinity with μand sites and moderate binding towards δreceptors. In ligand-stimulated [ 35 S] GTPgS binding studies, the N-methyl congener acted as a potent and full agonist at the μreceptor. The two N-allyl derivatives showed antagonistic effects at μand 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,δand opioid receptors. Acknowledgements Supported by the Hungarian Research Fund (K81701) and the Austrian Science Fund (FWF: P15481 and TRP 19-B18). Author details 1 Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary. 2 Department of Pharmaceutical Chemistry, Institute of Pharmacy, and Center for Molecular Biosciences, University of Innsbruck, 6020 Innsbruck, Austria. Published: 5 September 2011 doi:10.1186/1471-2210-11-S2-A13 Cite this article as: Sipos et al.: Development of novel N-methyl and N-allyl-substituted oxazolomorphinans and their interaction with opioid receptors. BMC Pharmacology 2011 11(Suppl 2):A13. * Correspondence: [email protected].at 1 Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary Full list of author information is available at the end of the article Sipos et al.BMC Pharmacology 2011, 11(Suppl 2):A13 http://www.biomedcentral.com/1471-2210/11/S2/A13 © 2011 Sipos 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.