title: Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists.
abstract: A novel series of N-(phenylalkyl)cinnamides related to N-(4-phenylbutyl)-3,4-dihydroxy-beta-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. 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 N-(phenylalkyl)cinnamides are selective antagonists of NR1A/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC(50) value of 77 nM and >1000-fold selectivity with respect to NR1A/2A and NR1A/2C receptors. Potency at alpha(1) adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1A/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.
authors.affiliation: Department of Chemistry, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Tamiz
authors.forename: S X
authors.initials: SX
authors.lastname: Cai
authors.forename: Z L
authors.initials: ZL
authors.lastname: Zhou
authors.forename: P W
authors.initials: PW
authors.lastname: Yuen
authors.forename: R M
authors.initials: RM
authors.lastname: Schelkun
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: E
authors.initials: E
authors.lastname: Weber
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: J F
authors.initials: JF
authors.lastname: Keana
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D009865:Oocytes; D011869:Radioligand Assay; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000577:Amides; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D018691:Excitatory Amino Acid Antagonists; D018719:Erb-b2 Receptor Tyrosine Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C121217:N-(4-phenylbutyl)-4-hydroxycinnamide; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C064740:epidermal growth factor receptor-neu receptor