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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
22
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pubmed:dateCreated |
1993-12-10
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pubmed:abstractText |
3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antagonist activity. Generally poor potency at the glycine site is observed when a variety of electron-withdrawing substituents are attached to the 3-position of 3,4-dihydro-2(1H)-quinolones. The analogues 5-9 (IC50 values > 100 microM, Table I) exist largely in the 3,4-dipseudoaxial conformation (as evidenced by 1H NMR spectra), whereas the 3-cyano derivative (10, IC50 = 12.0 microM) has a relatively high population of the 3-pseudoequatorial conformer. The 3-nitro analogue (4, IC50 = 1.32 microM) has a pKa approximately 5 and thus exists at physiological pH as an anion with the nitro group planar to the quinolone ring. The general requirement of acidity for high affinity binding at the glycine/NMDA site is supported with the good activity of the other 3-nitro derivatives (13-21), all of which are deprotonated at physiological pH. The 3-nitro-3,4-dihydro-2(1H)-quinolones and 2-carboxy-1,2,3,4-tetrahydroquinolines show quite different structure-activity relationships at the 4-position. The unselective excitatory amino acid activity of 21 is comparable with 6,7-dichloro-quinoxaline-2,3-dione and 6,7-dichloroquinoxalic acid and this suggests similarities in their modes of binding to excitatory amino acid receptors. The broad spectrum excitatory amino acid antagonist activity of the 4-unsubstituted analogue 21 (KbNMDA = 6.7 microM, KbAMPA = 9.2 microM) and the glycine/NMDA selectivity of the other 3-nitro derivatives allows the proposal of a model for AMPA receptor binding which differs from the glycine binding pharmacophore in that there is bulk intolerance adjacent to the 4-position. Compound 21 (L-698,544) is active (ED50 = 13.2 mg/kg) in the DBA/2 mouse anticonvulsant model and is the most potent combined glycine/NMDA-AMPA antagonist yet reported, in vivo, and may prove to be a useful pharmacological tool.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Nitro Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Quinolones,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, AMPA,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, N-Methyl-D-Aspartate
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
36
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pubmed:owner |
NLM
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pubmed:authorsComplete |
N
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pubmed:pagination |
3397-408
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:8230130-Amino Acids,
pubmed-meshheading:8230130-Animals,
pubmed-meshheading:8230130-Binding Sites,
pubmed-meshheading:8230130-Chemistry, Physical,
pubmed-meshheading:8230130-Glycine,
pubmed-meshheading:8230130-Nitro Compounds,
pubmed-meshheading:8230130-Physicochemical Phenomena,
pubmed-meshheading:8230130-Quinolones,
pubmed-meshheading:8230130-Rats,
pubmed-meshheading:8230130-Receptors, AMPA,
pubmed-meshheading:8230130-Receptors, N-Methyl-D-Aspartate,
pubmed-meshheading:8230130-Structure-Activity Relationship
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pubmed:year |
1993
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pubmed:articleTitle |
3-Nitro-3,4-dihydro-2(1H)-quinolones. Excitatory amino acid antagonists acting at glycine-site NMDA and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.
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pubmed:affiliation |
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
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pubmed:publicationType |
Journal Article
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