Using transfected NIH 3T3 mouse fibroblast cell lines expressing the rat 5-HT2A and rat 5-HT2C receptor subtypes, and techniques of 2-[125I](+)-iodolysergic acid diethylamide ([125I]LSD) binding and serotonin (5-hydroxytryptamine, 5-HT)-stimulated phosphoinositide hydrolysis, we have characterized a new structural class of 5-HT receptor ligands, the aryloxyalkylimidazolines. These compounds were found to be potent competitors of [125I]LSD binding at both receptor subtypes (Ki approximately 5-200 nM) and to have efficacy ranging from potent competitive antagonists (IC50 approximately 25 nM) to moderately potent full agonists (EC50 approximately 200 nM). Some of these compounds are agonists at both receptor subtypes, while others are 5-HT2C receptor agonists with 5-HT2A receptor antagonist activity. None of the aryloxyalkylimidazolines reported here have 5-HT2A or 5-HT2C receptor selective antagonist activity. Since these compounds are novel structures, we compared them with a variety of reference 5-HT receptor ligands selected from other chemical classes that have previously been studied at 5-HT2A and 5-HT2C receptors in native tissues.