Structure-activity Relationships for a Series of Bis(phenylalkyl)amines: Potent Subtype-Selective Inhibitors of N-methyl-D-aspartate Receptors

J Med Chem. 1998 Aug 27;41(18):3499-506. doi: 10.1021/jm980235+.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butylamines* / chemical synthesis
  • Butylamines* / chemistry
  • Butylamines* / pharmacology
  • Excitatory Amino Acid Antagonists* / chemical synthesis
  • Excitatory Amino Acid Antagonists* / chemistry
  • Excitatory Amino Acid Antagonists* / pharmacology
  • Nylidrin / pharmacology
  • Oocytes
  • Phenols* / chemical synthesis
  • Phenols* / chemistry
  • Phenols* / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / biosynthesis
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / biosynthesis
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • Butylamines
  • Excitatory Amino Acid Antagonists
  • N-(2-(4-hydroxyphenyl)ethyl)-5-phenylpentylamine
  • Phenols
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Nylidrin