title: Mechanism of inhibition of the GluA1 AMPA receptor channel opening by the 2,3-benzodiazepine compound GYKI 52466 and a N-methyl-carbamoyl derivative.
abstract: 2,3-Benzodiazepine derivatives, also known as GYKI compounds, represent a group of the most promising synthetic inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Here we investigate the mechanism of inhibition of the GluA1 channel opening and the site of inhibition by GYKI 52466 and its N-3 methyl-carbamoyl derivative, which we term as BDZ-f. GluA1 is a key AMPA receptor subunit involved in the brain function. Excessive activity and elevated expression of GluA1, however, has been implicated in a number of neurological disorders. Using a laser-pulse photolysis technique, which provides ∼60 μs resolution, we measured the effect of these inhibitors on the rate of GluA1 channel opening and the amplitude of the glutamate-induced whole-cell current. We found that both compounds inhibit GluA1 channel noncompetitively. Addition of an N-3 methyl-carbamoyl group to the diazepine ring with the azomethine feature (i.e., GYKI 52466) improves the potency of the resulting compound or BDZ-f without changing the site of binding. This site, which we previously termed as the "M" site on the GluA2 AMPA receptor subunit, therefore favorably accommodates an N-3 acylating group. On the basis of the magnitude of the inhibition constants for the same inhibitors but different receptors, the "M" sites on GluA1 and GuA2 are different. Overall, the "M" site or the binding environment on GluA2 accommodates the same compounds better, or the same inhibitors show stronger potency on GluA2, as we have reported previously [ Wang et al. Biochemistry ( 2011 ) 50 , 7284 - 7293 ]. However, acylating the N-3 position to occupy the N-3 side pocket of the "M" site can significantly narrow the difference and improve the potency of a resulting compound on GluA1.
authors.affiliation: Department of Chemistry, and Center for Neuroscience Research, University at Albany, SUNY , Albany, New York 12222, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wu
authors.forename: Congzhou
authors.initials: C
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Niu
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
chemical_list: D001569:Benzodiazepines; D018091:Receptors, AMPA; C061950:GYKI 52466; C118651:GYKI 53784
references.citation: Neurobiol Aging. 1999 May-Jun;20(3):287-95
references.pmid: 10588576
references.citation: ACS Chem Neurosci. 2011 May 12;2(9):506-513
references.pmid: 22059113
references.citation: Biochemistry. 2003 Oct 28;42(42):12367-75
references.pmid: 14567698
references.citation: Neuropathology. 2010 Apr;30(2):182-8
references.pmid: 20102521
references.citation: Pharmacol Rev. 1999 Mar;51(1):7-61
references.pmid: 10049997
references.citation: Biochemistry. 2012 Feb 28;51(8):1787-95
references.pmid: 22304561
references.citation: Biochemistry. 2010 Nov 2;49(43):9207-16
references.pmid: 20863077
references.citation: J Neurosci. 2009 Mar 11;29(10):3206-19
references.pmid: 19279258
references.citation: Bioorg Med Chem Lett. 2003 Feb 10;13(3):443-6
references.pmid: 12565947
references.citation: Eur J Neurosci. 2009 Mar;29(6):1141-52
references.pmid: 19302150
references.citation: Nature. 2000 Jun 22;405(6789):955-9
references.pmid: 10879537
references.citation: J Mol Med (Berl). 2005 Feb;83(2):110-20
references.pmid: 15624111
references.citation: J Neurosci. 2013 Jan 23;33(4):1577-88
references.pmid: 23345231
references.citation: Eur J Neurosci. 2008 Jun;27(12):3161-70
references.pmid: 18598260
references.citation: Prog Brain Res. 1998;116:371-83
references.pmid: 9932389
references.citation: Cell. 2001 May 4;105(3):331-43
references.pmid: 11348590
references.citation: Farmaco. 1996 Apr;51(4):269-74
references.pmid: 8645414
references.citation: Biochemistry. 2005 Apr 19;44(15):5835-41
references.pmid: 15823042
references.citation: Biochemistry. 2007 Feb 20;46(7):2027-36
references.pmid: 17256974
references.citation: J Neurosci. 1996 Nov 1;16(21):6634-47
references.pmid: 8824304
references.citation: J Biol Chem. 2004 Feb 6;279(6):3990-7
references.pmid: 14610080
references.citation: J Biol Chem. 2000 Jul 14;275(28):21355-63
references.pmid: 10748170
references.citation: Science. 1997 Jun 27;276(5321):2042-5
references.pmid: 9197267
references.citation: J Neurosci. 1996 Mar 15;16(6):1982-9
references.pmid: 8604042
references.citation: Biochemistry. 2008 Jan 22;47(3):1061-9
references.pmid: 18161947
references.citation: Pharmacol Rev. 2010 Sep;62(3):405-96
references.pmid: 20716669
references.citation: Biochemistry. 2011 Aug 23;50(33):7284-93
references.pmid: 21751782
references.citation: ACS Chem Neurosci. 2013 Apr 17;4(4):635-44
references.pmid: 23402301
references.citation: J Neurosci. 2008 Jul 9;28(28):7084-90
references.pmid: 18614677
references.citation: Mini Rev Med Chem. 2001 Sep;1(3):243-53
references.pmid: 12369971
references.citation: Mol Pharmacol. 1998 Mar;53(3):590-6
references.pmid: 9495827
references.citation: Science. 1999 Jun 11;284(5421):1805-11
references.pmid: 10364547
references.citation: Psychol Rev. 1992 Apr;99(2):195-231
references.pmid: 1594723
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3269-74
references.pmid: 10077673
references.citation: Med Chem. 2005 Sep;1(5):481-5
references.pmid: 16787333
references.citation: Curr Pharm Des. 2002;8(10):913-39
references.pmid: 11945139
references.citation: Biochemistry. 2003 Oct 28;42(42):12358-66
references.pmid: 14567697
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Sep;6(3):131-44
references.pmid: 16183555
references.citation: J Physiol. 2003 Dec 15;553(Pt 3):843-56
references.pmid: 14555717
references.citation: ACS Chem Neurosci. 2014 Feb 19;5(2):138-47
references.pmid: 24313227