NOVEL (4-PHENYLPIPERIDINYL)ALKYL AND (4-PHENYLPIPERAZINYL)ALKYL SPACED ESTERS OF 1-PHENYLCYCLOPENTANECARBOXYLIC ACIDS AS POTENT SIGMA-SELECTIVE COMPOUNDS

A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl) alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for aff inity at sigma(1) and sigma(2) sites by inhibition of [H-3]-(+)-pentaz ocine (PENT) and [H-3]-1,3-di(2-tolyl)guanidine (DTG) binding in guine a pig brain. The phenylpiperidines were more potent sigma ligands than the corresponding piperazines. Structural modifications varying the o ptimal spatial distance between the piperidine nitrogen and ester func tions led to the identification of the propyl compound 24 ([H-3]PENT K -i = 0.50 nM; [H-3]DTG K-i = 1.17 nM) and the butyl derivative 32 ([H- 3]PENT K-i = 0.51 nM; [H-3]DTG K-i = 0.69 nM) as novel high-affinity s igma-selective agents. An ethylene spacer was optimum with para-substi tuted analogs. A notable finding was the discovery of 2-(4-phenylpiper idinyl) ethyl 1-(4-nitrophenyl)cyclopentanecarboxylate hydrochloride ( 15) (RLH-033), which demonstrated potent affinity for the [H-3]PENT-de fined sigma site with a K-i of 50 pM, selectivity for sigma(1) over mu scarinic M(1) (> 17600-fold), M(2) (> 34200-fold), dopamine D-1 (> 580 00-fold), and D-2 (> 7000-fold) receptors, and inactivity at phencycli dine, NMDA, and opioid receptors. RLH-033 is a valuable tool which wil l aid further in understanding the biology of the sigma recognition si te. Information from this research has further defined the topography of the sigma recognition site, which may provide an explanation for th e diverse structures which bind with relatively high affinity.