NEUROTROPHIC 3,9-BIS[(ALKYLTHIO)METHYL]-K-252A AND 3,9-BIS(ALKOXYMETHYL)-K-252A DERIVATIVES

A series of 3,9-disubstituted [(alkylthio)methyl]- and (alkoxymethyl)- K-252a derivatives was synthesized with the aim of enhancing and separ ating the neurotrophic properties from the undesirable NGF (trh A kina se) and PKC inhibitory activities of K-252a. Data from this series rev eal that substitution in the 3- and 9-positions of K-252a with these g roups reduces trh A kinase inhibitory properties approximately 100- to >500-fold while maintaining or in certain cases enhancing the neurotr ophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K252a ( 8) was identified as a potent and selective neurotrophic agent in vitr o 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 kina se C, 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 degenerati on 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.