title: Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors.
abstract: We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline-containing analogs. Compounds were evaluated using both two-electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits AMPA, kainate, and GABA or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors.
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Rose M
authors.initials: RM
authors.lastname: Santangelo Freel
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ogden
authors.forename: Katie L
authors.initials: KL
authors.lastname: Strong
authors.forename: Alpa
authors.initials: A
authors.lastname: Khatri
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Chepiga
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Jensen
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
mesh_terms: D000818:Animals; D002460:Cell Line; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008956:Models, Chemical; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; D018698:Glutamic Acid; D005998:Glycine