A novel series of 2-(1,2,4-oxadiazol-5-yl)-1H-indole derivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered. Systematic modification of our original lead by changing the pendant functional groups, linker, heterocyclic core, and basic side chain revealed the structure-activity requirements for this novel template and resulted in the identification of more potent analog with improved potency as compared to the parent compound.