| Autor: |
Guzikowski, A. P., Tamiz, A. P., Acosta-Burruel, M., Hong-Bae, S., Cai, S. X., Hawkinson, J. E., Keana, J. F. W., Kesten, S. R., Shipp, C. T., Tran, M., Whittemore, E. R., Woodward, R. M., Wright, J. L., Zhou, Z.-L. |
| Zdroj: |
Journal of Medicinal Chemistry; March 9, 2000, Vol. 43 Issue: 5 p984-994, 11p |
| Abstrakt: |
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. |
| Databáze: |
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