title: Comparative studies of anthraquinone- and anthracene-tetraamines as blockers of N-methyl-D-aspartate receptors.
abstract: Anthraquinone spermine [N1-(anthraquinone-2-carbonyl)spermine; AQ343], anthraquinone homospermine [N1-(anthraquinone-2-carbonyl; AQ444], anthracene spermine [N1-(9-anthracenylmethyl)spermine; Ant343], and anthracene homospermine [N1-(9-anthracenylmethyl)homospermine; Ant444] were found to be potent antagonists of recombinant N-methyl-D-aspartate (NMDA) receptors (NRs). The effects of both anthraquinone (AQ)- and anthracene (Ant)-tetraamines were reversible and voltage-dependent. Results of experiments using mutant NR1 and NR2B subunits of NMDA receptor identified residues that influence block by AQ- and Ant-tetraamines. The results indicate that the polyamine tail is crucial for block by AQ- and Ant-tetraamines. Residues in the outer vestibule of the NR1 subunit were more strongly involved in block by AQ-and Ant-tetraamines than residues in the corresponding region of NR2B. Several amino acid residues in the inner vestibule, below the level of the selectivity filter of NR1 and NR2B, affected block by AQ444, Ant343, and Ant444, but they did not affect block by AQ343. AQ-tetraamines could permeate the channel at very negative membrane potentials when the narrowest constriction of the channel was expanded by replacing the Asn residue at Asn616 of NR1 and NR2B with Gly, whereas Ant-tetraamines did not easily pass through the channel, apparently because of differences in the relative position of the head groups on AQ- and Ant-polyamines.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Miki
authors.initials: M
authors.lastname: Takigawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katagiri
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomitori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishimura
authors.forename: Navneet
authors.initials: N
authors.lastname: Kaur
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
authors.forename: Mariko
authors.initials: M
authors.lastname: Kitajima
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takayama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.forename: Keith
authors.initials: K
authors.lastname: Williams
authors.forename: Keiko
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Kazuei
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000880:Anthraquinones / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011073:Polyamines / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D000880:Anthraquinones; D018691:Excitatory Amino Acid Antagonists; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate