| 摘要 |
The invention relates to cholecystokinin (CCK) derivatives of the general formula I: P-L-Xl-X2-X3-Gly-Trp-X6-DMeAsp-X8-NH2, wherein P is Chem. 1 : HOOC-(CH2)x-CO-*, wherein x is an integer in the range of 12-18; L is absent, or L comprises at least one linker element selected from Chem. 2 : *-NH-CH(COOH)-(CH2)2-CO-*, Chem. 3 : *-NH- (CH2)2-[O-(CH2)2]k-O-[CH2]n-CO-* wherein k is an integer in the range of 1-11 and n is an integer in the range of 1-5, Chem. 4: *-NH-CH(CH2OH)-CO-*, Chem. 5 : *-NH-CH2- CO-*, and/or Chem. 6: *-NH-CH[(CH2)4-NH2]-CO-*; XI is absent, Asp, DAsp, bAsp, DbAsp, Glu, or DGIu; X2 is Phe(4-sulfomethyl) or sTyr; X3 is NIe, Leu, Ala, He, Lys, Arg, Pro, Met, Phe, Ser, His, or Val; X6 is NIe, He, Gin, Met, Met (02), Leu, Val, Pro, Hpg, or Ala; X8 is Phe, MePhe, INal, MelNal, 2Nal, Me2Nal, Trp, or MeTrp. The invention also relates to the corresponding CCK peptides, as well as to methods for preparing the peptides and the derivatives. The invention also relates to pharmaceutical compositions and uses of the derivatives, in particular for treatment of obesity and related health problems, where the compounds may be used either alone or in combination with other weight reducing agents and optionally in addition to diet and exercise. The derivatives have a high potency on the CCK-1 receptor (CCK-1R), a high selectivity for the CCK-1R as compared to the CCK-2R, effect on food intake in vivo, very long half-lives, and are chemically very stable. |
