4-hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl) piperidine: A novel, potent, and selective NR1/2B NMDA receptor antagonist

A structure-based search and screen of our compound library identified N-(2 -phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combi nation (IC50 = 0.63 mu M). We report on the optimization of this lead compo und in terms of potency, side effect liability, and in vivo activity. Poten cy was assayed by electrical recordings in Xenopus oocytes expressing clone d rat NMDA receptors. Side effect liability was assessed by measuring affin ity for alpha(1)-adrenergic receptors and inhibition of neuronal K+ channel s. Central bioavailability was gauged indirectly by determining anticonvuls ant activity in a mouse maximal electroshock (MES) assay. Making progressiv e modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a similar to 25-fold increase in NR1A/2B potency (IC50 = 0.025 mu M). p-Methyl substitution on the benzyl ring (10b ) produced a similar to 3-fold increase in MES activity (ED50 = 0.7 mg/kg i v). Introduction of a second hydroxyl group into the C-4 position on the pi peridine ring (10e) resulted in a substantial decrease in affinity for alph a(1) receptors and reduction in inhibition of Kf channels with only a modes t decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(methylbenzyl)piperidine, Co 10 1244/PD 174494) had the optimum pharmacological profile and was selected fo r further biological evaluation.