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

• Published in: Journal of medicinal chemistry 2000-03, Vol.43 (5), p.984-994
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; Biological and medical sciences; Cerebral Cortex - metabolism; Corpus Striatum - metabolism; Electroshock; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - metabolism; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); In Vitro Techniques; Male; Medical sciences; Mice; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oocytes - physiology; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Dopamine - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Seizures - drug therapy; Seizures - etiology; Xenopus laevis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990428c

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.