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- Blomberg, David, et al.
(author)
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Synthesis and biological evaluation of leucine enkephalin turn mimetics
- 2006
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In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:3, s. 416-423
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Journal article (peer-reviewed)abstract
- A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1–4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a β-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to µ- and δ-opioid receptors in rat brain membranes. With the exception of the β-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the µ- and δ-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1–4) β-turn.
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2. |
- Blomberg, David, et al.
(author)
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Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
- 2004
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In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 69:10, s. 3500-3508
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Journal article (peer-reviewed)abstract
- A β-turn mimetic in which the four amino acids of a β-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular COi − HNi+3 hydrogen bond that is often found in β-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a β-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a β-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on 1H NMR data showed that the β-turn mimetic was flexible, but that it resembled a type-II β-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.
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