Novel (4-Phenylpiperidinyl)- and (4-Phenylpiperazinyl)alkyl-Spaced Esters of 1-Phenylcyclopentanecarboxylic Acids as Potent σ-Selective Compounds

A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at σ₁ and σ₂ 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 σ 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 K_i = 0.50 nM; [³H]DTG K_i = 1.17 nM) and the butyl derivative 32 ([³H]PENT K_i = 0.51 nM; [³H]DTG K_i = 0.69 nM) as novel high-affinity σ-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 σ site with a K_i of 50 pM, selectivity for σ₁ 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 σ recognition site. Information from this research has further defined the topography of the σ recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.