MU OPIOID RECEPTOR AGONIST ANALOGS OF THE ENDOMORPHINS

摘要

The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic pentapeptide and hexapeptide analogs of endomorphin that have (i) a carboxy-terminal extension with an amidated amino acid and (ii) a D-amino acid substitution in position 2. These peptide analogs exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.

主权项

1. A cyclic peptide of Formula I:(I)H-Tyr-cyclo[X1-X2-X3-X4]-X5,wherein
X1 and X4 each independently is an acidic D-amino acid or a basic D-amino acid; X2 and X3 each independently is an aromatic amino acid; X5 is selected from the group consisting of Ala-NHR, Arg-NHR, Asn-NHR, Asp-NHR, Cys-NHR, Glu-NHR, Gln-NHR, Gly-NHR, His-NHR, Ile-NHR, Leu-NHR, Met-NHR, Orn-NHR, Phe-NHR, Pro-NHR, Ser-NHR, Thr-NHR, Trp-NHR, Tyr-NHR, and Val-NHR,wherein R is H or an alkyl group; and
there is an amide bond between an amino group and a carboxylic acid group on side chains of amino acids X1 and X4; with the proviso that when X1 is an acidic amino acid, then X4 is a basic amino acid; and when X1 is a basic amino acid, then X4 is an acidic amino acid.