%0 Journal Article
%T , -Dimethylphenylalanine: A Useful Aromatic Amino Acid Surrogate for Tyr or Phe Residue in Opioid Peptides
%A Yusuke Sasaki
%A Akihiro Ambo
%J International Journal of Medicinal Chemistry
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/498901
%X Two aromatic amino acids, Tyr1 and Phe3 or Phe4, are important structural elements in opioid peptides because they interact with opioid receptors. The usefulness of an artificial amino acid residue , -dimethylphenylalanine (Dmp) was investigated as an aromatic amino acid surrogate for several opioid peptides, including enkephalin, dermorphin, deltorphin, endomorphin, dynorphin A, and nociceptin peptides. In most peptides, substitutions of Phe3 by a Dmp residue produced analogs with improved receptor-binding affinity and selectivity, while the same substitution of Phe4 induced markedly reduced receptor affinity and selectivity. Interestingly, replacement of Tyr1 by Dmp produced analogs with unexpectedly high affinity or produced only a slight drop in receptor affinity and bioactivity for most peptides. Thus, Dmp is also a useful surrogate for the N-terminal Tyr residue in opioid peptides despite the lack of a phenolic hydroxyl group, which is considered necessary for opioid activity. The Dmp1-substituted analogs are superior to , -dimethyltyrosine (Dmt)1-substituted analogs for high receptor selectivity since the latter generally have poor receptor selectivity. Thus, Dmp is very useful as an aromatic amino acid surrogate in opioid peptides and may be useful for developing other novel peptide mimetics with high receptor specificity. 1. Introduction Three major types of opioid receptors, ¦Ì, ¦Ä, and ¦Ê, have been cloned and assigned to the superfamily of rhodopsin-like G-protein-coupled receptors [1¨C3]. The ¦Ì-receptors are involved in supraspinal analgesia, respiratory depression, euphoria, sedation, decreased gastrointestinal motility, and physical dependence [4]. The ¦Ä-receptors appear to affect cardiovascular function, contribute to analgesia, and cause changes in affective behavior [4]. The ¦Ê-receptors are responsible for spinal analgesia, miosis, a modest degree of sedation, and some respiratory depression [4]. In vivo, opioid peptides exert pharmacological actions via the opioid receptors. Enkephalins (Tyr-Gly-Gly-Phe-Leu/Met) [5] and endomorphins (Tyr-Pro-Phe/Trp-Phe-NH2) [6] are endogenous ligands for the ¦Ä- and ¦Ì-opioid receptors, respectively. Dynorphin A (DYN: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln) is the endogenous ligand of the ¦Ê-opioid receptor [7]. Dermorphin (DM, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) [8] and [D-Ala2]deltorphin II (DT, Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2) [9] are naturally occurring opioid peptides isolated from South American frogs and possess high selectivity toward ¦Ì- and ¦Ä-opioid receptors,
%U http://www.hindawi.com/journals/ijmc/2012/498901/