Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (+/-)-3-(4-hydroxyphenyl)pyrrolidines: Selective antagonists at the 1A/2B NMDA receptor subtype

Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typical ly small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an omega-phenylalkyl substituent on the heterocyclic nitrogen. Many of the se antagonists, for example ifenprodil (1), incorporate a ii-hydroxy substi tuent on the omega-phenyl group. In this study, the position of this 4-hydr oxy substituent was transferred from the w-phenyl group to the benzyl or ph enyl group located on the 4-position of the piperidine ring. Analogues inco rporating pyrrolidine in lieu of piperidine were also prepared, Electrical recordings using cloned receptors expressed in Xenopus oocytes show that hi gh-potency antagonists at the NR1A/2B subtype are obtained employing N-(ome ga-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine,4-(4-hydroxybenzy l)piperidine, and(+/-)-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC50 = 0.022 mu M), 33 (IC50 = 0.059 mu M), and 40 (IC50 = 0.017 mu M), re spectively. 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 bin ding affinities of 21 at alpha(1)-adrenergic receptors ([H-3]prazosin, IC50 = 0.54 mu M) and dopamine D2 receptors ([H-3]raclopride, IC50 = 1.2 mu M) are reduced by incorporating a hydroxy group onto the 4-position of the pip eridine ring and the beta-carbon of the N-alkyl spacer to give (+/-)-27: IC 50 NR1A/2B, 0.026; alpha(1), 14; D2, 105 mu M. The high-potency phenolic an tagonist 21 and its low-potency O-methylated analogue 18 are both potent an ticonvulsants in a mouse maximal electroshock-induced seizure (MES) study ( ED50 (iv)= 0.23 and 0.56 mg/kg, respectively). These data indicate that suc h compounds penetrate the blood-brain barrier but their MES activity may no t be related to NMDA receptor antagonism.