Bifunctional analgesic compounds for opioid receptor agonists and neurokinin-1 receptor antagonists
AssigneeUniversity of Arizona
InventorsVictor Hruby, Padma Nair, Takashi Yamamoto
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Abstract
The present invention provides a novel chimeric compound comprising an agonist opioid receptor binding moiety at its N-terminus and an antagonist neurokinin-1 (NK1) receptor binding moiety at its C-terminus for producing analgesia, a pharmaceutical composition comprising the chimeric compound, a method of making the compound, and a method of treating pain using the novel chimeric compounds.
Claims43
A chimeric compound of formula (1) comprising an agonist opioid receptor binding moiety at its N-terminus and an antagonist neurokinin-1 (NK1) receptor binding moiety at its C-terminus,
- X1-X2-X3-X4-X5-X6-X7-X8-Trp-R1-R2 (SEQ ID NO:
- 7) formula (1)
- wherein:
- X1 is absent or is Tyr or substituted Tyr;
- X2 is absent or is Gly or D-amino acid;
- X3 is absent or is Gly;
- X4 is Phe or substituted Phe;
- X5 is Phe, Leu, Met, Gly, DPhe, Nle, Nle(R3), DCys, Cys, Ser(O—R4), substituted Cys, or substituted DCys;
- X6 is absent or is Pro, Ala, DLeu, DPro, Ser(O—R4) or Aib;
- X7 is absent or is Leu, Cys, DCys, Ser(O—R4), Pen, DPen, Ala, DAla, beta Ala, alpha Abu, gamma Abu, Ava, or Aib;
- X8 is absent or is Ser(O—R4);
- R1 is O, NH, or N—R5;
- R2 is benzyl (Bzl) or substituted benzyl;
- R3 is alkyl or a substituted alkyl;
- R4 is sugar;
- R5 is alkyl or substituted alkyl, or salts thereof,
- wherein the chimeric compound is optionally a cyclic compound,
- wherein the C-terminus moiety optionally comprises an antagonist of substance P,
- with the proviso that the chimeric compound is not
- Tyr-DAla-Gly-Phe-Gly-Trp-O-Bzl(CF3)2 and Tyr-DAla-Gly-Phe-Ala-Trp-O-Bzl(CF3)2,
- wherein the compound induces analgesia.
A chimeric compound of formula (2) comprising an agonist opioid receptor binding moiety at its N-terminus and an antagonist neurokinin-1 (NK1) receptor binding moiety at its C-terminus,
- X1-X2-X3-X4-X5-X6-X7-X8-Trp-R1-R2 (SEQ ID NO:
- 8) formula (2)
- wherein:
- X1 is absent or is Tyr or Dmt(2′,6′-dimethyl-L-tyrosine);
- X2 is absent or is Gly, DAla, DCyc, or DPhe;
- X3 is absent or is Gly;
- X4 is Phe, pClPhe, pFPhe, pBrPhe, or DPhe;
- X5 is Phe, Leu, Met, Gly, DPhe, Nle, Nle(NMe), DCys, Cys, Ser(OGlc), Pen, or DPen;
- X6 is absent or is Pro, Ala, DLeu, DPro, Ser(OGlc) or Aib;
- X7 is absent or is Leu, Cys, DCys, Ser(OGlc), Pen, DPen, Ala, DAla, beta Ala, alpha Abu, gamma Abu, Ava, or Aib;
- X8 is absent or is Ser(OGlc);
- R1 is O, NH, or NMe;
- and
- R2 is Bzl;
- 3′,5′-Bzl(CF3)2;
- Bzl-3′-(CF3);
- 3′,5′-Bzl(OMe)2;
- Bzl-2′,4′-(OMe)2, or salts thereof,
- with the proviso that the chimeric compound is not
- Tyr-DAla-Gly-Phe-Gly-Trp-O-Bzl(CF3)2 and Tyr-DAla-Gly-Phe-Ala-Trp-O-Bzl(CF3)2,
- wherein the compound induces analgesia.
Dependencies are inferred from the claim text.