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Synthesis and biological evaluation of novel peripherally active morphiceptin analogs
Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
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2010 (English)In: Peptides, ISSN 0196-9781, Vol. 31, no 8, p. 1617-1624Article in journal (Refereed) Published
Abstract [en]

Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a tetrapeptide present in the enzymatic digest of bovine beta-casein,is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 13. Two of the obtained analogs, [Dmt1, d-Ala2, d-1-Nal3]morphiceptin and [Dmt1, d-NMeAla2, d-1-Nal3]morphiceptin (Dmt2,6-dimethyltyrosine andd-1-Nal3-(1-naphthyl)-d-alanine)) displayed very high -receptor affinity, resistance to enzymaticdegradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test afterintracerebroventricular but not intravenous administration, which indicated that they could not cross the bloodbrain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility.Wereport that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception,inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome

Place, publisher, year, edition, pages
Amsterdam: Elsevier , 2010. Vol. 31, no 8, p. 1617-1624
National Category
Biological Sciences
Research subject
Biomedical Science
Identifiers
URN: urn:nbn:se:kau:diva-10571DOI: 10.1016/j.peptides.2010.04.018OAI: oai:DiVA.org:kau-10571DiVA, id: diva2:494114
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2015-06-25Bibliographically approved

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Publisher's full texthttp://www.ncbi.nlm.nih.gov/pubmed/20434497http://www.sciencedirect.com.ezproxy.ub.gu.se/science?_ob=MImg&_imagekey=B6T0M-4YYRMFF-1-K&_cdi=4866&_user=646099&_pii=S0196978110001725&_origin=browse&_zone=rslt_list_item&_coverDate=08%2F31%2F2010&_sk=999689991&wchp=dGLbVtz-zSkzV&md5=8fdeb53da876738b9e3

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