Synthesis and structure-activity relationships of dipeptoid amides as potent and selective nonpeptide antagonists of the human glucagon receptor. We report here the design, synthesis, biological evaluation and structure-activity relationships of potent, selective and metabolically stable glucagon receptor antagonists. The screening data showed that the N-terminal tetrapeptoid 1 could be used as the model to replace the N-terminal dipeptide part of the natural hormone for glucagon receptor antagonists. Compound 15 with a spacer of 2 amino acid units of Glu-Ala in its structure had the highest binding affinity for the human glucagon receptor with a K(i) value of 0.2 nM and a selectivity of 6400-fold versus the human glucagon receptor as well as other related receptors such as the ghrelin receptor, the oxytocin receptor, the adrenocorticotropin receptor, the corticotropin-releasing factor receptor 1, the luteinizing hormone/choriogonadotropin receptor and the thyroid stimulating hormone receptor. Compound 15 is currently being developed for the treatment of type 2 diabetes.