Conformationally constrained cyclic enkephalin analogs with delta receptor specificity.

摘要

Novel compounds which are capable of binding with enhanced specificity to the delta receptor are disclosed. The compounds are a series of cyclic, conformationally constrained analogs of enkephalins which display exceptional delta receptor specificity. The compounds of the present invention are polypeptides of the formula:
<Chemistry id="chema01" num="0001"><Image id="ia01" he="41" wi="59" file="IMGA0001.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R' and R<Sup>2</Sup>, which may be the same or different, are hydrogen, methyl, or lower alkyl having 1 to 5 carbon atoms;
<UnorderedLists id="ula01" listStyle="none"><ListItem>R<Sup>3</Sup> and R<Sup>4</Sup>, which may be the same or different, are hydrogen, methyl, or lower alkyl having 1 to 5 carbon atoms, provided, however, that R<Sup>1</Sup>, R<Sup>2</Sup>, R<Sup>3</Sup>, and R<Sup>4</Sup> may not all be hydrogen when both n and m are zero;</ListItem><ListItem>R<Sup>5</Sup> is hydrogen, L-tyrosine, D-tyrosine, or L-tyrosine or D-tyrosine substituted on the Na-amino with 1 or 2 lower alkyl or alkenyl groups;</ListItem><ListItem>R<Sup>6</Sup> is a substituted or unsubstituted aromatic;</ListItem><ListItem>R<Sup>7</Sup> is hydrogen or methyl;</ListItem><ListItem>R<Sup>8</Sup> is carboxylate, carboxamide or amino acid residue; provided, however, that where m and n are zero; and R' and R<Sup>2</Sup> are both methyl groups; and R<Sup>3</Sup> and R<Sup>4</Sup> are both hydrogen; and R<Sup>7</Sup> is hydrogen; R<Sup>8</Sup> is an amino acid residue;</ListItem><ListItem>X and Y are hydrogen or methyl; and,</ListItem><ListItem>n and m, which may be the same or different, are 0 or 1.</ListItem></UnorderedLists>

The novel compounds include those which have either agonist or antagonist activity. The compounds may be used to induce pharmacological or therapeutic effects, including analgesia, in humans and other animals.