Fifteen naphthalenic bioisosteres of melatonin with variations on the N-acylamino group have been synthesized. The results provide new structure-binding relationship information for the melatonin receptor and introduce new tools for studying melatonin's physiological importance. The indole nucleus of melatonin can be substituted by naphthalene without losing binding potency. Structural variations of the N-acylamino group significantly affect binding affinity: increasing the acyl chain length to propyl (7) or butyl (8) increases affinity, further homologation or branching decreases it, and a cyclopropyl substituent (compound 13) gives the highest affinity (Kd = 3 × 10⁻¹³). The cyclopropyl group's importance is confirmed by the indolyl analogue (compound 20) showing 100-fold higher affinity. Some ligands have greater affinity than melatonin and similar in vivo biological activities. Studies on their ability to re-entrain rat activity rhythms are ongoing. Additionally, a new serotonin receptor subtype (5-HT4) was recently identified in brain and gut tissues, positively coupled to adenylate cyclase. Metoclopramide's gastroprokinetic activity and cisapride's activity are correlated with 5-HT4 agonism. SC-53116 is the first selective agonist at the 5-HT4 receptor subtype, which may be useful for treating gastrointestinal and CNS disorders.