Iododimethyltyrosine: A building block for mu-opioid receptor-selective peptides

WCC 10

Alison D. Oostendorp, alisono@gmail.com1, Yu Lu2, Emily Fergason2, Galina Toneva2, Fabio Gallazzi, GallazziF@missouri.edu3, Susan Z. Lever, LeverS@missouri.edu4, and John R. Lever5. (1) Department of Chemistry, Elmhurst College, 190 Prospect Ave, 1673, Elmhrust, IL 60126, (2) University of Missouri-Columbia, (3) Molecular Biology Program, University of Missouri-Columbia, 125 Chemistry, 601 S. College Avenue, Columbia, MO 65211, (4) Department of Chemistry, University of Missouri-Columbia, 601 S. College Ave., Columbia, MO 65211, (5) Departments of Radiology, Medical Pharmacology and Physiology, and Radiopharmaceutical Sciences Institute, University of Missouri - Columbia, Harry S. Truman Veterans, Administration Medical Center, 800 Hospital Drive, Columbia, MO 65201
We have synthesized a novel tetrapeptide, H-Dmt-D-Ala-Phe-Orn-NH2 (ClogP = - 0.10) that has very high binding affinity for mu opioid receptors in vitro (0.033 0.01 nM; guinea pig brain), and displays excellent selectivity for mu opioid receptors over the kappa or delta types (kappa / mu = 1003; delta / mu = 7788). An iodinated Dmt-D-Ala-Phe-Orn-NH2 may be useful for in vitro studies when labeled with 125I, and for in vivo studies when labeled with 123I. The non-radiolabeled peptide is a measurement of opioid receptor affinity and selectivity. We report that bis(pyridine)iodonium tetrafluoroborate is a useful reagent to prepare mono-iodinated dimethyltyrosine. Initial studies showed mono-iodination of Fmoc-protected dimethyltyrosine as confirmed by reversed-phase HPLC, 1H-NMR, 13C-NMR and MALDI-TOF MS. This material was used to prepare a sample of iodinated H-Dmt-D-Ala-Phe-Orn-NH2 (ClogP = 0.72) by standard solid-phase peptide synthesis. The final target was characterized by HPLC-MS ([M+H]1+: Calcd. 667.2; Found: 667.1).

The Merck Index Women in Chemistry
2:30 PM-4:30 PM, Monday, August 18, 2008 Pennsylvania Convention Center -- Hall C, Poster

Women Chemists Committee

The 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008