Linked Life Data

12540236

Source:http://linkedlifedata.com/resource/pubmed/id/12540236

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2003-1-23
pubmed:abstractText
Protein kinase C (PKC) is known to participate in the processing of the amyloid precursor protein (APP). Abnormal processing of APP through the action of the beta- and gamma-secretases leads to the production of the 39-43 amino acid Abeta fragment, which is neurotoxic and which is believed to play an important role in the etiology of Alzheimer's disease. PKC activation enhances alpha-secretase activity, which results in a decrease of the amyloidogenic products of beta-secretase. In this article, we describe the synthesis of 10 new benzolactam V8 based PKC activators having side chains of varied saturation and lipophilicity linked to the aromatic ring through an amide group. The K(i) values measured for the inhibition of phorbol ester binding to PKCalpha are in the nanomolar range and show some correlation with their lipophilicity. Compounds 5g and 5h show the best binding affinity among the 10 benzolactams that were synthesized. By use of a cell line derived from an AD patient, significant enhancement of sAPPalpha secretion was achieved at 1 microM concentration for most of the compounds studied and at 0.1 microM for compounds 5e and 5f. At 1 microM the enhancement of sAPPalpha secretion for compounds 5c-h is higher than that observed for the control compound 8-(1-decynyl)benzolactam (BL). Of interest is the absence of activity found for the highly lipophilic ligand 5i, which has a K(i) of 11 nM. On the other hand, its saturated counterpart 5j, which possesses a comparable K(i) and ClogP, retains activity in the secretase assay. In the hyperplasia studies, 5f showed a modest response at 100 microg and 5e at 300 microg, suggesting that 5f was approximately 30-fold less potent than the PKC activator mezerein and 100-fold less potent than TPA. 5e was approximately 3-fold less active than 5f. On the basis of the effect of unsaturation for other potent PKC ligands, we would predict that 5e would retain biological activity in most assays but would show a marked loss of tumor-promoting activity. Compound 5e thus becomes a viable candidate compound in the search for Alzheimer's therapeutics capable of modulating amyloid processing.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
364-73
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPalpha.
pubmed:affiliation
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, D.C. 20007-2197, USA. kozikowa@georgetown.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.