A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.