Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules that consist of a 4-benzyl-or a 4-phenylpiperidine with an ω-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the ω-phenyl group. In this study, the position of this 4-hydroxy substituent was transferred from the ω-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(ωphenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (()-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC 50 ) 0.022 µM), 33 (IC 50 ) 0.059 µM), and 40 (IC 50 ) 0.017 µM), respectively. These high-potency antagonists are >1000 times more potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding affinities of 21 at R 1 -adrenergic receptors ([ 3 H]prazosin, IC 50 ) 0.54 µM) and dopamine D2 receptors ([ 3 H]raclopride, IC 50 ) 1.2 µM) are reduced by incorporating a hydroxy group onto the 4-position of the piperidine ring and the β-carbon of the N-alkyl spacer to give (()-27: IC 50 NR1A/2B, 0.026; R 1 , 14; D2, 105 µM. The high-potency phenolic antagonist 21 and its lowpotency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock-induced seizure (MES) study (ED 50 (iv) ) 0.23 and 0.56 mg/kg, respectively). These data indicate that such compounds penetrate the blood-brain barrier but their MES activity may not be related to NMDA receptor antagonism.