Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.
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.
Department of Chemistry, University of Oregon, Eugene, Oregon 97403, USA.
A P
AP
Tamiz
E R
ER
Whittemore
Z L
ZL
Zhou
J C
JC
Huang
J A
JA
Drewe
J C
JC
Chen
S X
SX
Cai
E
E
Weber
R M
RM
Woodward
J F
JF
Keana
D000818:Animals; D002082:Butylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009756:Nylidrin / Q000494:pharmacology; D009865:Oocytes; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D002082:Butylamines; D018691:Excitatory Amino Acid Antagonists; C114193:N-(2-(4-hydroxyphenyl)ethyl)-5-phenylpentylamine; D010636:Phenols; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D009756:Nylidrin