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

Article abstract of DOI:10.1021/jm00039a008

A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at ?₁ and ?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 ? 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 ?-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 ? site with a K_i of 50 pM, selectivity for ?₁ over muscarinic M₁ (>17600-fold), M₂ (>34200-fold), dopamine D₁ (>58000-fold), and D₂ (>7000-fold) receptors, and inactivity at phenylcyclidine, NMDA, and opioid receptors. RLH-033 is a valuable tool which will aid further in understanding the biology of the ? recognition site. Information from this research has further defined the topography of the ? recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.