Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics.

From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.

Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.

From an HTS hit, a series of potent and selective inhibitors of GSK3beta have been designed based on a Cdk2-homology model and with the help of several crystal structures of the compounds within Cdk2.

Localization of presenilin-1 mRNA in rat brain.

We examined the regional and cellular distribution of presenilin-1 gene expression in the rat brain by in situ hybridization. Microscopic analysis demonstrated that presenilin-1 mRNA is predominantly expressed in areas such as the occipital cortex, the pyramidal layer of the hippocampus, thalamic nuclei and the cerebellar granular layer. The expression of presenilin-1 is mostly neuronal: only a weak hybridization signal was found in the corpus callosum and in the astrocytoma cell lines U373MG and U138MG.

Cloning, pharmacological characterization, and anatomical distribution of a rat cDNA encoding for a galanin receptor.

We have cloned and expressed a rat cDNA, designated GALR1-rat, that encodes a galanin receptor based on homology, pharmacology, and anatomical criteria. This cDNA was isolated from a rat brain cDNA library. The nucleotide sequence of the cloned receptor revealed an open reading frame encoding a 346-amino-acid protein, showing 90.

Neurotensin increases tyrosine hydroxylase messenger RNA-positive neurons in substantia nigra after retrograde axonal transport.

In previous studies we have shown that labelled neurotensin injected into the rat striatum was found to be transported retrogradely in dopaminergic neurons through a process which was receptor and microtubule dependent. Now, we show, by in situ hybridization, the consequences of the striatal injection of neurotensin on the gene expression of tyrosine hydroxylase in the substantia nigra. Rats were injected with neurotensin or its fragments in the striatum of one side and with saline or the inactive fragment on the other.