title: Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.
abstract: Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia, USA.
authors.forename: Yesim A
authors.initials: YA
authors.lastname: Tahirovic
authors.forename: Matthew
authors.initials: M
authors.lastname: Geballe
authors.forename: Ewa
authors.initials: E
authors.lastname: Gruszecka-Kowalik
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Myers
authors.forename: Polina
authors.initials: P
authors.lastname: Lyuboslavsky
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Adam
authors.initials: A
authors.lastname: French
authors.forename: Hasan
authors.initials: H
authors.lastname: Irier
authors.forename: Woo-Baeg
authors.initials: WB
authors.lastname: Choi
authors.forename: Keith
authors.initials: K
authors.lastname: Easterling
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Robert
authors.initials: R
authors.lastname: Kotloski
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009043:Motor Activity / Q000187:drug effects; D011412:Propanolamines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D011412:Propanolamines; D016194:Receptors, N-Methyl-D-Aspartate
references.citation: J Physiol. 1996 Dec 15;497 ( Pt 3):761-72
references.pmid: 9003561
references.citation: Eur J Pharmacol. 1979 May 1;55(3):323-6
references.pmid: 37098
references.citation: Eur J Pharmacol. 1989 Aug 3;166(3):359-66
references.pmid: 2553433
references.citation: Pharmacotherapy. 1996 Jan-Feb;16(1):82-93
references.pmid: 8700797
references.citation: Pharmacol Rev. 1999 Mar;51(1):7-61
references.pmid: 10049997
references.citation: Nature. 2000 Feb 10;403(6770):614-5
references.pmid: 10688187
references.citation: J Neurochem. 1998 May;70(5):2120-8
references.pmid: 9572299
references.citation: Ann Neurol. 1988 Oct;24(4):543-51
references.pmid: 2853604
references.citation: J Neurosurg. 1997 Dec;87(6):921-6
references.pmid: 9384405
references.citation: Neuron. 1999 May;23(1):171-80
references.pmid: 10402203
references.citation: Crit Care Med. 1997 Jun;25(6):1037-43
references.pmid: 9201058
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13019-24
references.pmid: 14559973
references.citation: Science. 2004 Mar 19;303(5665):1813-8
references.pmid: 15031495
references.citation: J Comput Aided Mol Des. 2005 Sep-Oct;19(9-10):661-86
references.pmid: 16328855
references.citation: J Neurosci. 1998 Aug 15;18(16):6163-75
references.pmid: 9698310
references.citation: Curr Drug Targets CNS Neurol Disord. 2005 Apr;4(2):143-51
references.pmid: 15857299
references.citation: Brain Res Brain Res Rev. 1995 Feb;20(2):250-67
references.pmid: 7795658
references.citation: Trends Neurosci. 1999 Sep;22(9):391-7
references.pmid: 10441299
references.citation: J Neurosci. 2002 Jul 15;22(14):5955-65
references.pmid: 12122058
references.citation: J Med Chem. 2007 Jan 11;50(1):74-82
references.pmid: 17201411
references.citation: Nat Neurosci. 1998 Dec;1(8):659-67
references.pmid: 10196581
references.citation: Exp Neurol. 2004 May;187(1):86-93
references.pmid: 15081591
references.citation: Mol Pharmacol. 1999 Jun;55(6):957-69
references.pmid: 10347236
references.citation: J Pharmacol Exp Ther. 1999 Sep;290(3):1393-408
references.pmid: 10454519
references.citation: Curr Med Chem. 2004 Feb;11(3):389-96
references.pmid: 14965239
references.citation: J Pharmacol Exp Ther. 2002 Sep;302(3):940-8
references.pmid: 12183650
references.citation: Psychopharmacology (Berl). 2005 Apr;179(1):4-29
references.pmid: 15731895
references.citation: Curr Pharm Des. 1999 May;5(5):381-404
references.pmid: 10213801
references.citation: Nature. 1991 Nov 7;354(6348):31-7
references.pmid: 1834949
references.citation: J Neurosci. 1987 Feb;7(2):357-68
references.pmid: 2880937
references.citation: Neuron. 1994 Mar;12(3):529-40
references.pmid: 7512349
references.citation: J Med Chem. 1995 Aug 4;38(16):3138-45
references.pmid: 7636876
references.citation: J Neurosci. 2005 Jan 12;25(2):308-17
references.pmid: 15647474
references.citation: J Med Chem. 1999 Aug 26;42(17):3412-20
references.pmid: 10464027
references.citation: Bioorg Med Chem Lett. 2003 Feb 24;13(4):693-6
references.pmid: 12639560
references.citation: Eur J Pharmacol. 1989 Aug 11;167(1):127-35
references.pmid: 2550253
references.citation: Psychopharmacology (Berl). 2004 Dec;177(1-2):61-7
references.pmid: 15316716
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11062-7
references.pmid: 10984504
references.citation: Science. 1956 Jul 6;124(3210):29-31
references.pmid: 13337345
references.citation: Br J Pharmacol. 1992 Aug;106(4):958-65
references.pmid: 1393293
references.citation: Eur J Pharmacol. 2001 Oct 26;430(1):147-8
references.pmid: 11698075
references.citation: J Comput Aided Mol Des. 2004 Jul-Sep;18(7-9):451-74
references.pmid: 15729846
references.citation: Curr Med Chem. 2001 Sep;8(11):1275-89
references.pmid: 11562266
references.citation: Bioorg Med Chem Lett. 2004 Aug 2;14(15):3953-6
references.pmid: 15225705
references.citation: J Med Chem. 2004 Apr 8;47(8):2089-96
references.pmid: 15056006
references.citation: J Neurosci Methods. 1987 May;20(1):83-90
references.pmid: 2884353
references.citation: Neuron. 2000 Dec;28(3):911-25
references.pmid: 11163276
references.citation: Bioorg Med Chem Lett. 2003 Nov 3;13(21):3859-61
references.pmid: 14552795
references.citation: Mol Pharmacol. 1996 Dec;50(6):1541-50
references.pmid: 8967976
references.citation: Biochem Biophys Res Commun. 1992 Jun 30;185(3):826-32
references.pmid: 1352681
references.citation: Neuropharmacology. 1999 Feb;38(2):243-51
references.pmid: 10218865
references.citation: Mol Pharmacol. 1993 Oct;44(4):851-9
references.pmid: 7901753
references.citation: Chemistry. 2000 Jun 16;6(12):2200-4
references.pmid: 10926226
references.citation: J Neuropathol Exp Neurol. 1996 Jan;55(1):1-13
references.pmid: 8558164
references.citation: Science. 1992 May 22;256(5060):1217-21
references.pmid: 1350383
references.citation: J Med Chem. 2000 Jul 13;43(14):2609-45
references.pmid: 10893301
references.citation: Neuropharmacology. 1999 May;38(5):611-23
references.pmid: 10340299
references.citation: Prog Neurobiol. 1995 Dec;47(6):477-511
references.pmid: 8787032
references.citation: Chem Biol. 2005 Apr;12(4):427-37
references.pmid: 15850979
references.citation: Curr Top Med Chem. 2006;6(7):697-709
references.pmid: 16719810
references.citation: Protein Sci. 2005 Sep;14(9):2275-83
references.pmid: 16131656
references.citation: Br J Pharmacol. 1998 Feb;123(3):463-72
references.pmid: 9504387
references.citation: J Pharmacol Exp Ther. 1997 Dec;283(3):1285-92
references.pmid: 9400004
references.citation: Crit Rev Neurobiol. 2004;16(3):187-224
references.pmid: 15701057