The Biological Consequences of Replacing d‐Ala in Biphalin with Amphiphilic α‐Alkylserines |
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Authors: | Oliwia Fr?czak Anika Lasota Anna Le?niak Andrzej W Lipkowski Aleksandra Olma |
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Institution: | 1. Institute of Organic Chemistry, Lodz University of Technology, , 90‐924 ?ód?, Poland;2. Mossakowski Medical Research Centre, Polish Academy of Sciences, , 01‐793 Warsaw, Poland |
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Abstract: | Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α‐alkylserines in position 2 and 2′. The incorporation of bulky α,α‐disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O,N‐migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor‐binding assay in the rat brain using 3H]DAMGO (a μ ligand) and 3H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α‐alkylserine, as analogues containing (R)‐α‐alkylserines displayed higher μ receptor affinity and selectivity than those incorporating the (S)‐isomers. |
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Keywords: | amphiphilic amino acids biphalin analogues O N‐migration O‐acyl isopeptides opioid activities opioid peptides α ‐alkylserines |
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