In order to investigate the structural requirements for a cycloalkyl moiety in the potent hallucinogen 1-(1-phenylcyclohexyl)piperidine (PCP, 1), a series of structural analogues was synthesized in which the size of the cycloalkyl ring was varied from three carbons to eight carbons. Biological activities of these compounds were assessed in an in vitro assay (phencyclidine binding assay) and an in vivo assay (discriminative stimulus assay). As the cycloalkyl ring size decreased from that of cyclohexane (PCP), PCP-like activity declined in both assays, but as the cycloalkyl ring size became larger than cyclohexane, a sharp decline in PCP-like activity was observed in the in vivo assay, while activity in the in vitro assay was only slightly less than that of PCP. 1-(1-Phenylcyclooctyl)piperidine (8) had potent competitive binding properties in the in vitro binding assay but produced no observable PCP-like effects in the in vivo assay. The importance of the cycloalkyl ring in the structure of PCP was demonstrated by testing benzylpiperidine (2), which had almost no measurable activity in either assay.