Alpha-conotoxin peptides

A method for providing musculoskeletal relaxation in a patient undergoing a surgical procedure requiring anesthesia which comprises administering an effective amount of an α-conotoxin peptide or a pharmaceutically acceptable salt thereof, said α-conotoxin peptide having the general formula I or general formula II:

• Formula I:
• Xaa1-Xaa2-Xaa3-Xaa4-Cys-Cys-Xaa5-Xaa6-Xaa7-Cys-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Cys-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa22Xaa23-Xaa24-Xaa25 (SEQ ID NO:
• 1), wherein Xaa1 is des-Xaa1 or Gly;
• Xaa2 is des-Xaa2, Asn, Arg, Asp, Ser, Thr, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa3 is des-Xaa3, Gly, Glu or γ-carboxy-Glu (Gla);
• Xaa4, is des-Xaa4, Glu, Gla, Gln, pyro-Glu, Arg, Ile Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Cys, His, halo-His, any unnatural hydroxy containing amino acid (such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr), Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa5 is His, Asn or halo-His;
• Xaa6 is Pro or hyroxy-Pro;
• Xaa7 is Ala, Gly, Ser or Thr;
• Xaa8 is Gly or Ala;
• Xaa9 is Arg, Lys, Pro, hydroxy-Pro, Gly, Gln, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa10 is His, halo-His, Asn, Lys, Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, ornithine or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa11 is Tyr, Phe, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid (such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr), Trp (D or L), halo-Trp, neo-Trp, or any unnatural aromatic amino acid (such as nitro-Phe, 4-substituted-Phe wherein the substituent is C1-C3 alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO, —CN, —SO3H and -NHAc);
• Xaa12 is Ile, Ser, Thr, Asp, Gly, Asn, Glu, Gla or Val;
• Xaa13 is des-Xaa13, Lys, Arg, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa14 is des-Xaa14, Gly, Lys, Arg, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa15 is des-Xaa15, Gly, Thr, Ser, His, halo-His, Lys, Arg, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa16 is des-Xaa16, Ser or Thr;
• Xaa17 is des-Xaa17 or Cys;
• Xaa18 is des-Xaa18, Ser or Thr;
• Xaa19 is des-Xaa19, Arg, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa20 is des-Xaa20, Thr, Ser, Pro or hydroxy-Pro;
• Xaa21is des-Xaa21, Leu, Ser or Thr;
• Xaa22 is des-Xaa22, Glu or Gla;
• Xaa23 is des-Xaa23, Pro or hydroxy-Pro;
• Xaa24 is des-Xaa24, Arg, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa25 is des-Xaa25, Arg, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• and the C-terminus may contain a free carboxyl group or an amide group;
• Formula II:
• Xaa1-Xaa2-Xaa3-Cys-Cys-Xaa4-Xaa5-Xaa6-Xaa7-Cys-Xaa8-Xaa9-Xaa10-Xaa11-Xaa6-Xaa12-Ile-Cys-Xaa13-Xaa14-Xaa15 (SEQ ID NO:2), wherein, Xaa1 is des-Xaa1, Arg, Ser, Thr, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa2 is des-Xaa2, Asp, Gly, Leu, Arg, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa3 is des-Xaa3, Pro, hydroxy-Pro, Ala, Gly or Leu;
• Xaa4 is Tyr, Ser, Thr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid (such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr);
• Xaa5 is His, Asn, Ile, Tyr, halo-His, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr;
• Xaa6 is Pro or hydroxy-Pro;
• Xaa7 is Thr, Ala, Val, Ser, Pro or hydroxy-Pro;
• Xaa8 is Asn, Thr, Ser, Lys, Arg, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg);
• Xaa9 is Met, Val, Ala, Leu or Ile;
• Xaa10 is Ser, Thr, Asn, His or halo-His;
• Xaa11 is Asn, Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, or any unnatural hydroxy containing amino acid (such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr);
• Xaa12 is Glu, γ-carboxy-Glu (Gla), Gln or Asp;
• Xaa13 is des-Xaa13 or Gly;
• Xaa14 is des-Xaa14 or Gly;
• Xaa15 is des-Xaa15, Arg, Lys, ornithine, homoargine, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid (such as N-1-(2-pyrazolinyl)-Arg) and the C-terminus may contain a free carboxyl group or an amide group.