We investigated the effects of phencyclidine (PCP), a psychotomimetic dissociative anesthetic, and several related drugs on voltage-dependent K + currents in PC12 cells, a neuron-like clonal cell line derived from a rat pheochromocytoma. Whole-cell voltage clamp recordings demonstrated two kinetically distinct voltage-dependent outward (K +) current components in these cells: a rapidly activating and inactivating component, I A, that was selectively eliminated by 4-aminopyridine (2 mM) and a slowly activating, minimally inactivating (sustained) component, I K, that was specifically blocked by tetraethylammonium (20 mM). PCP (1–100 μM) produced a dose-dependent blockade of both I K and I A, however, at low doses the drug selectively reduced I K with little effect on I A; the IC 50s for blockade of I K and I A were 4 and 25 μM, respectively. The blockade of I K was voltage-dependent so that the degree of block decreased with increasing depolarization, indicating that the blocking mechanism is likely one in which the positively charged PCP molecule is drawn into the channel pore. Several PCP related drugs also suppressed I K. Thienyl-PCP (TCP), a drug that is behaviorally more potent than PCP, partially blocked I K at low doses (31% at 1μM), but even at high doses (25μM) the degree of block was never as great as that produced by PCP. The optically active PCP congeners (+)-PCMP(1-(1-phenylcyclohexyl)-3-methyl-piperidine) and dexoxadrol were also potent blockers of I K. However, in contrast to the stereospecificity these compounds demonstrate in binding to high-affinity PCP receptors and in eliciting PCP-like behavioral responses, their enantiomers (−)-PCMP and levoxadrol showed similar potencies as the parent compounds in blocking I K. These results demonstrate that PCP and related drugs are powerful, selective blockers of I K in PC12 cells. The structure-activity studies indicate that this effect occurs at a site that is pharmacologically distinct from the behaviorally relevant PCP receptor. Blockade of K + channels is unlikely to be responsible for the psychotomimetic or anticonvulsant properties of PCP, but could account for the convulsant potential of the drug.