Compounds for control of appetite
This invention relates generally to peptides including tripeptides and to methods for pharmaceutical treatment of mammals using such tripeptides and analogs thereof. More specifically, the invention is directed to neuropeptide Y (“NPY”) receptor antagonists and agonists including O-glycosylated tripeptides, i.e. O-glycopeptides, and extended tripeptides, and their analogs, as well as to PYY analogs, to pharmaceutical compositions containing such tripeptides and PYY analogs, and to methods of treatment of mammals using such tripeptides and PYY analogs. In addition, the invention relates to methods of treatment of mammals using such tripeptides and PYY analogs for control of appetite, blood pressure, cardiovascular response, libido, and circadian rhythm.
1. A method for controlling an NPY mediated physiological response in a subject comprising administering to said subject a compound having the formula:
R8-linker[A1-A2-A3] n -W
wherein:
R8 is H-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-(SEQ. ID. NO.1), H-[X(Y)] n -where X is Ser, Thr, or Tyr, Y is β-D-Glc or β-D-Gal, and n is 1, 2, or 3,
(SEQ. ID. NO. 9), Ac-Arg-Tyr-Arg-Gly-Asp-Leu-Gly-Leu-Gly-Arg-Arg (SEQ. ID. NO. 10), or
SEQ. ID. NO. 11);
A1 is a D or L-amino acid selected from Cys, Leu, Dap, Trp, Gln, a tethered amino acid with an indole ring, Phe, Hyp, a Trp derivative; C α Me-Trp, C α Me-Gln, Des-amino-Trp, Pyr, Bth, Nal, Tcc, Asn, Nva, Abu, Ser, Tyr, Tic-OH, Phe, Tip, and Dip;
Linker is a compound that forms a peptide bond with A1 and forms one of either a peptide or ester bond with R8;
A2 is a D or L-amino acid selected from Gly, Cys, Trp, Arg, N-Me-Arg, C α Me-Arg, Orn, Cit, hArg(R)2 where R is selected from hydrogen, alkyl, aryl, aralkyl, or alkylaryl, Lys-ε-NH-R where R is selected from hydrogen, alkyl, aryl, aralkyl, or alkylaryl;
A3 is a D or L-amino acid selected from Glu, Tyr, N-Me-Tyr, C α Me-Tyr, Tic-OH, Tic, Dip, Trp, Phe, des-carboxylic-Tyr, and Tyr-(R) where R is hydrogen or a lipophilic group;
n=1, 2 or 3
W is —OH, —N-R3R4, or OR5 where R3, R4, and R5, independently, is H, C1-C12 alkyl, C6-C18 aryl, C1-C12 acyl, C7-C18 aralkyl, or C7-C18 alkaryl; or a pharmaceutically acceptable salt thereof; and
each bond between two amino acids or amino acid derivatives, represented by a dash (“-”), can be either a peptide bond or a pseudopeptide bond; or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is H-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-NH—CH 2 —CH 2 —CO-Trp-Arg-Tyr-N H 2 (SEQ. ID. NO. 12).
3. The method of claim 1 , wherein administering to said subject comprises administering to said subject the compound together with a pharmaceutically acceptable carrier substance, which defines a therapeutic composition, in a therapeutically effective amount to control the NPY mediated physiological response.
4. The method of claim 3 , wherein the composition is capable of suppressing appetite.
5. The method of claim 3 , wherein the composition is in the form of a pill, tablet, or capsule for oral administration to a subject.
6. The method of claim 3 , wherein the composition is in the form of a liquid for oral administration to a subject.
7. The method of claim 3 , wherein the composition is in the form of a liquid for nasal administration as drops or spray to a subject.
8. The method of claim 3 , wherein the composition is in the form of a liquid for intravenous, subcutaneous, parenteral, or intraperitoneal administration to a subject.
9. The method of claim 3 , wherein the composition is in the form of a biodegradable sustained-release composition for intramuscular administration to a subject.
10. The method of claim 3 , wherein the composition includes a lipophilic salt and is suitable for administration in the form of an oil emulsion or dispersion to a subject.
11. The method of claim 1 , wherein the compound defines a pharmaceutically acceptable salt.