Synthesis of galmic: A nonpeptide galanin receptor agonist
- Susana Conde Ceide*,†,
- Laurent Trembleau*,†,
- Gebhard Haberhauer*,†,
- Laszlo Somogyi*,†,
- Xiaoying Lu‡,
- Tamas Bartfai‡, and
- Julius Rebek, Jr.*,†,§
- Departments of *Chemistry and ‡Neuropharmacology and †The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
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Contributed by Julius Rebek, Jr., October 11, 2004
Abstract
Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: jrebek{at}scripps.edu.
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Author contributions: J.R. designed research; X.L. contributed new reagents/analytic tools; S.C.C., L.T., G.H., L.S., and T.B. performed research; and J.R. wrote the paper.
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Abbreviations: Boc, t-butyloxycarbonyl; DEPT, distortionless enhancement by polarization transfer; DCM, dichloromethane; DIEA, N,N-diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide; EDCI, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; FTMS, Fourier transform MS; HOBt, N-hydroxybenzotriazole; RT, room temperature; TFA, trifluoroacetic acid.
- Copyright © 2004, The National Academy of Sciences
