Magnus Wilhelm Walter

Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.

Structure-based design of agrochemicals

This review covers recent advances in the structure-based design of agrochemicals. The three main sectors of agrochemistry, i.e. herbicides, insecticides, and fungicides are covered. The literature in this field to the present date is reviewed and 88 references are cited.

Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

From serendipity to design - making agrochemicals to order

Magnus Walter who worked for several years at Jealotts Hill Research Station (formerly Zeneca Agrochemicals, now Syngenta Crop Protection) describes recent advances in the structure-based design of agrochemicals.

Synthesis of 11C-labeled (S,S)-CFMME and (R)-OHDMI and their evaluation as candidate radioligands for imaging norepinephrine transporters with PET

Introduction: (R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro2-methoxy-phenyl)-1-morpholin-2-yl-ethanol ((S,S)-CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake (inhibitory constants (K is) were 8.29 and 10.8 nM for (R)-OHDMI and (S,S)-CFMME, respectively, as compared with (S,S)-2-(a-(2methoxyphenoxy)benzyl)morpholine (S,S)-MeNER) which has a Ki of 7.93 nM). Here, we have explored the labeling of these ligands with carbon-11 for evaluation as candidate radioligands for imaging central norepinephrine transporters (NET).