Rene Wyler

Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands.

In humans, nicotine has been demonstrated to improve both normal and disordered attention, suggesting potential clinical utility for nicotinic ligands. However, attempts to replicate these findings in the rodent have met with some difficulty, thus hampering the search for specific receptor mechanisms underlying these effects. In the present studies, we sought to characterize the effects of nicotine and subtype-selective ligands in a group of aged rats, which show consistent deficits in sustained attention over prolonged sessions of responding in the five-choice serial reaction time task (5-CSRTT). Following the establishment of a replicable performance improvement with nicotine (0.4 mg/kg), we assessed the effects of both SIB 1765F (1–5 mg/kg) and AR-R17779 (20 mg/kg), agonist ligands with selective affinities for the α4β2 and α7 receptor sites, respectively. We then attempted to block this effect of nicotine using the high affinity, competitive nicotinic antagonist DHβE (3 mg/kg). Finally, in an attempt to determine whether the psychostimulant profile of nicotinic agonists could be dissociated from their effects on attention, we compared the (R)- and (S)-enantiomers of SIB 1765F in the 5-CSRTT, and in their ability to increase locomotor activity. Reversal of a within-session decline in performance speed and accuracy by nicotine was mimicked by SIB 1765F, but not by AR-R17779, whereas DHβE antagonized all of the performance changes induced by nicotine. Finally, the (S)- but not the (R)-enantiomer increased locomotor activity and improved performance in the 5-CSRTT. These results support a critical involvement for the α4β2 nicotinic receptor in mediating the attention-enhancing properties of nicotine.

4-Aminoquinolines as a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.

1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines, a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.

Discovery of (R)-1-[2-Hydroxy-3-(4-hydroxy-phenyl)-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol: A Novel NR1/2B Subtype Selective NMDA Receptor Antagonist

Starting from Ro-25-6981 as a lead compound, highly potent and selective NR1/2B subtype selective NMDA receptor antagonists, with low activity at alpha(1) adrenergic receptors were developed.

4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists.

A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.

Sembragiline: a novel, selective monoamine oxidase type B inhibitor for the treatment of Alzheimer’s disease

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.

2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists

Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.

2-Styryl-pyridines and 2-(3,4-Dihydro-naphthalen-2-yl)pyridines as Potent NR1/2B Subtype Selective NMDA Receptor Antagonists

A series of 2-styryl-pyridines and 2-(3,4-dihydro-naphthalen-2-yl)-pyridines was prepared and evaluated as NR½B subtype selective NMDA receptor antagonists. The SAR developed in this series resulted in the discovery of high affinity antagonists that are selective (vs. α 1 and M 1 receptors) and are active in vivo.