1027837-67-7Relevant articles and documents
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
Guzikowski, Anthony P.,Tamiz, Amir P.,Acosta-Burruel, Manuel,Hong-Bae, Soo,Cai, Sui Xiong,Hawkinson, Jon E.,Keana, John F. W.,Kesten, Suzanne R.,Shipp, Christina T.,Tran, Minhtam,Whittemore, Edward R.,Woodward, Richard M.,Wright, Jon L.,Zhou, Zhang-Lin
, p. 984 - 994 (2000)
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-(ω-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4- hydroxybenzyl)piperidine, and (±)3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC50 = 0.022 μM), 33 (IC50 = 0.059 μM), and 40 (IC50 = 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 α1-adrenergic receptors ([3H]prazosin, IC50 = 0.54 μM) and dopamine D2 receptors ([3H]raclopride, IC50 = 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: IC50 NR1A/2B, 0.026; α1, 14; D2, 105 μM. The high-potency phenolic antagonist 21 and its low-potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock- induced seizure (MES) study (ED50 (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.
