Structure-activity studies with cholecystokinin: stereoisomers containing ortho-, meta- and para-tyrosine sulfate

Analogs of cholecystokinin (Ac-CCK-7) in which Tyr(SO3H) was replaced with D-Tyr(SO3H), Tyr(m-SO3H), D-Tyr(m-SO3H) Tyr(o-SO3H) and D-Tyr(o-SO3H) were prepared by solid phase peptide synthesis, characterized by amino acid analysis, MS, UV, IR and tested in vivo for their ability to suppress food intake and in vitro (receptor binding). Comparison of the binding efficacy to food intake revealed a poor correlation. Ac-[Tyr(m-SO3H)]-CCK-7 retained substantial anorectic activity, whereas Ac-[Tyr(o-SO3H)-CCK-7 was essentially inactive. Ac-[D-Tyr(SO3H)]-CCK-7 and Ac-[D-Tyr(mSO3H)]-CCK-7 retained substantial biological activity. From these studies we conclude that the position of the negative charge on Tyr (meta or para) is important for anorectic activity, but the chirality of the alpha-carbon is not important for biological activity.