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Neurotrophic 3,9-Bis[(alkylthio)methyl]- and -Bis(alkoxymethyl)-K-252a Derivatives
- Source :
- Journal of Medicinal Chemistry. 40:1863-1869
- Publication Year :
- 1997
- Publisher :
- American Chemical Society (ACS), 1997.
-
Abstract
- A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.
- Subjects :
- Indoles
Myosin light-chain kinase
Stereochemistry
Carbazoles
Apoptosis
Chick Embryo
Receptors, Nerve Growth Factor
Tropomyosin receptor kinase A
Choline O-Acetyltransferase
Indole Alkaloids
Prosencephalon
Substantia Innominata
Proto-Oncogene Proteins
Drug Discovery
Animals
Humans
Nerve Growth Factors
Enzyme Inhibitors
Receptor, trkA
Protein kinase A
Protein Kinase C
Protein kinase C
Motor Neurons
Neurons
biology
Chemistry
Kinase
Receptor Protein-Tyrosine Kinases
Rats
Nerve growth factor
Spinal Cord
Biochemistry
Enzyme inhibitor
Nerve Degeneration
biology.protein
Molecular Medicine
Female
Neurotrophin
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 40
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....22f12aa9d883ec35762af65701c19611