A group of peptide-based, long-acting, stable, highly selective cholecystokinin 1 receptor (CCK-1R) agonists with the potential to treat obesity has been identified and characterized, based on systematic investigation of synthetic CCK-8 analogues with N-terminal linkage to fatty acids. Sulfated Tyr in such compounds was stable in neutral buffer. CCK-1R selectivity was achieved mostly by introducing d- N-methyl-Asp instead of Asp at the penultimate position of CCK-8. Our compound 9 (NN9056) showed similar in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong reduction of food intake in lean pigs for up to 48 h after one subcutaneous injection without adverse effects, a plasma half-life of 113 h in minipigs after intravenous injection, and acceptable chemical stability in a neutral liquid formulation. In addition, we found a highly selective CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.