Linked Life Data

1674540

Source:http://linkedlifedata.com/resource/pubmed/id/1674540

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1991-6-26
pubmed:abstractText
The cyclopropyl compounds (Z)- and (E)-2-amino-2,3-methano-4-phosphonobutanoic acid, 5 and 6, respectively, were prepared as constrained analogues of 2-amino-4-phosphonobutanoic acid (AP4), a selective glutamate receptor ligand. A Horner-Emmons reaction of trimethyl N-(benzyloxycarbonyl)phosphonoglycinate with 2-(diethoxyphosphinyl)acetaldehyde gave the protected dehydroamino acids 9 and 10, which were individually subjected to the following sequence of reactions: cycloaddition of diazomethane, photoelimination of N2, and acid hydrolysis, to give 5 and 6, respectively. Extracellular recording techniques were used to evaluate the abilities of 5 and 6 to block evoked synaptic transmission in specific neuronal pathways of the rat hippocampal slice. In the lateral perforant path (LPP) 5 and 6 were equipotent and possessed IC50 values of 18 and 17 microM, respectively. In the medial perforant path (MPP), 6 (IC50 = 81 microM) was much more potent than 5 (IC50 = 1580 microM). In paired pulse experiments which differentiate presynaptic and postsynaptic inhibition, 5 and 6 enhanced the second response to the same extent as L-AP4, suggesting a presynaptic site of action for these compounds. In contrast, the cyclopentyl AP4 analogues 3 and 4 enhanced the second response to a lesser extent. It was concluded that the biologically active conformation of AP4 in the LPP is different than in the MPP. In order to explain the same potency of 5 and 6 in the LPP, it was postulated that the two analogues assume a conformation that allows their functional groups to occupy the same relative place in space. Molecular modeling showed that the best overlap was achieved when the alpha C-beta C-gamma C-P dihedral angle for 5 was in the range of 130 degrees to 180 degrees and that of 6 was in the range of -130 degrees to -180 degrees. The results suggest that the bioactive conformation of AP4 in the LPP is an extended one.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1692-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
Synthesis of the 2-amino-4-phosphonobutanoic acid analogues (E)- and (Z)-2-amino-2,3-methano-4-phosphonobutanoic acid and their evaluation as inhibitors of hippocampal excitatory neurotransmission.
pubmed:affiliation
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't