The purpose of this study was to evaluate the binding of N-substituted-oxazolidinone-based compounds against a panel of receptor subtypes. Literature reports suggest that the oxazolidinone nucleus is a suitable fragment for binding to GPCR receptors including adenosine, muscarinic and serotonin receptors. Previous studies involving oxazolidinone-based and chromone-based compounds previously synthesized in our laboratory exhibited low to moderate affinity for muscarinic receptors. Consequently, we decided to screen our oxazolidinone- and chromone-based compounds in GPCR receptor panels using a receptor radioligand binding assay. Test compounds were evaluated for affinity in the binding assays and those ligands exhibiting % specific inhibition >50% were selected for further evaluation (IC₅₀ and ultimately subtype selectivity). Preliminary binding evaluation of oxazolidinone-based compounds indicated that the oxazolidinone nucleus represents a novel chemical entity in serotonergic (5-HT) ligands. The novel ligands evaluated for 5-HT subtype selectivity were found to be selective towards the serotonin subtype 2b. A cyclopentyl substituted oxazolidinone-based ligand containing a diphenylmethylpiperazine fragment (Compound 51) was identified as a 5-HT2b ligand with an IC₅₀ of 41 nM. The synthesis and evaluation of our novel oxazolidinone-based 5-HT ligands will be presented along with a discussion of the structure-activity relationship data for the series. The compounds reported herein represent an interesting series of novel 5-HT ligands that warrant further study. The data provided herein will assist in the design of future 5-HT2b ligands possessing improved affinity and selectivity. Such compounds will be useful research tools to better understand the physiological role of the 5-HT2b receptor subtype.