Schizophrenia is a complex multifactorial disease with typically unmet medical need. Vasoactive intestinal peptide receptor 2 (VIPR2), also known as VPAC2, is a seven transmembrane heterotrimeric G protein-coupled receptor (GPCR) that binds two homologous neuropeptides with high affinity, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), and it has been considered an attractive drug target for development to treat schizophrenia. However, VIPR2 belongs to class-B GPCRs that are intractable targets for small molecules. We recently developed a novel peptide KS-133 with a relatively low molecular weight (about 1500 g/mol) and characteristic bicyclic structure. KS-133 possesses drug-like properties as follows: (a) high selectivity and a potent antagonist activity against VIPR2; (b) remarkable resistant to protease degradation, a common problem with peptides; (c) prevention of cognitive decline in a mouse model of psychiatric disorders. Our study is not only the first validation of the effects of a VIPR2 antagonist in disease animal models, but also a good example of drug discovery for class-B GPCRs.