15037-36-2Relevant articles and documents
Novel (4-Phenylpiperidinyl)- and (4-Phenylpiperazinyl)alkyl-Spaced Esters of 1-Phenylcyclopentanecarboxylic Acids as Potent ?-Selective Compounds
Hudkins, Robert L.,Mailman, Richard B.,DeHaven-Hudkins, Diane L.
, p. 1964 - 1970 (1994)
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 -(+)-pentazocine (PENT) and -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 (PENT Ki = 0.50 nM; DTG Ki = 1.17 nM) and the butyl derivative 32 (PENT Ki = 0.51 nM; DTG Ki = 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 PENT-defined ? site with a Ki 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.
