A jerk-based algorithm ACCEL for the accurate classification of sleep-wake states from arm acceleration.

Arm acceleration data have been used to measure sleep-wake rhythmicity. Although several methods have been developed for the accurate classification of sleep-wake episodes, a method with both high sensitivity and specificity has not been fully established. In this study, we developed an algorithm, named ACceleration-based Classification and Estimation of Long-term sleep-wake cycles (ACCEL) that classifies sleep and wake episodes using only raw accelerometer data, without relying on device-specific functions. The algorithm uses a derivative of triaxial acceleration (jerk), which can reduce individual differences in the variability of acceleration data. Applying a machine learning algorithm to the jerk data achieved sleep-wake classification with a high sensitivity (>90%) and specificity (>80%). A jerk-based analysis also succeeded in recording periodic activities consistent with pulse waves. Therefore, the ACCEL algorithm will be a useful method for large-scale sleep measurement using simple accelerometers in real-world settings.

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

Discovery of the alpha7 nicotinic acetylcholine receptor agonists. (R)-3'-(5-Chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one as a novel, potent, selective, and orally bioavailable ligand.

Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the alpha7 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'-(5-chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one (25). Compound 25 has potent binding affinity (K(i) = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha4beta2 and alpha1beta2gammadelta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.