A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at sigma 1 and sigma 2 sites by inhibition of [3H]-(+)-pentazocine (PENT) and [3H]-1,3-di(2-tolyl)guanidine (DTG) binding in guinea pig brain. The phenylpiperidines were more potent sigma ligands than the corresponding piperazines. Structural modifications varying the optimal spatial distance between the piperidine nitrogen and ester functions led to the identification of the propyl compound 24 ([3H]PENT Ki = 0.50 nM; [3H]DTG Ki = 1.17 nM) and the butyl derivative 32 ([3H]PENT Ki = 0.51 nM; [3H]DTG Ki = 0.69 nM) as novel high-affinity sigma-selective agents. An ethylene spacer was optimum with para-substituted analogs. A notable finding was the discovery of 2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)-cyclopentanecarboxylate hydrochloride (15) (RLH-033), which demonstrated potent affinity for the [3H]PENT-defined sigma site with a Ki of 50 pM, selectivity for sigma 1 over muscarinic M1 (> 17,600-fold), M2 (> 34,200-fold), dopamine D1 (> 58,000-fold), and D2 (> 7000-fold) receptors, and inactivity at phencyclidine, NMDA, and opioid receptors. RLH-033 is a valuable tool which will aid further in understanding the biology of the sigma recognition site. Information from this research has further defined the topography of the sigma recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.