Structure-activity relationships for a series of bis (phenylalkyl) amines: Potent subtype-selective inhibitors of N-methyl-D-aspartate receptors

Tamiz, A.P.; Whittemore, E.R.; Zhou, Z.L.; Huang, J.C.; Drewe, J.A.; Chen, J.C.; Cai, S.X.; Weber, E.; Woodward, R.M.; Keana, J.F.

Journal of Medicinal Chemistry 41(18): 3499-3506


ISSN/ISBN: 0022-2623
PMID: 9719603
DOI: 10.1021/jm980235+
Accession: 009470444

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A series of bis(phenylalkyl)amines, structural analogues of ifenprodil and nylidrin, were synthesized and tested for antagonism of N-methyl-D-aspartate (NMDA) receptors. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The bis(phenylalkyl)amines were selective antagonists of NR1A/2B receptors. Assayed under steady-state conditions, the most potent of these, N-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentylamine hydrochloride (20), has an IC50 value of 8 nM and >1000-fold selectivity with respect to NR1A/2A and NR1A/2C receptors. The structure-activity relationship of the bis(phenylalkyl)amine series indicates that the piperidine ring and alkyl chain substitutions common to NR2B-selective antagonists such as ifenprodil, CP 101,606, and Ro 25-6981 are not necessary to generate potent and selective ligands. The primary determinants of potency are the phenolic OH group, acting as a hydrogen bond donor, the distance between the two rings, and an electrostatic interaction between the receptor and the basic nitrogen atom. This study provides a framework for designing structurally novel NR2B-selective antagonists which may be useful for treatment of a variety of neurological disorders.