Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists.

A series of 2-aryloxy-4-alkoxy-pyridines ( 1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF 1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF 1 receptor antagonist with an IC 50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine- N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [ (3)H]- 2 as well as the structure-activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF 1 antagonists could be used clinically as antidepressant drugs.

2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists.

An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.

Effects of hypocretin-1 in 192-IgG-saporin-lesioned rats.

Hypocretin, also known as orexin, is a neuropeptide located in the perifornical region of the lateral hypothalamus; this region projects to all the major arousal centres including the basal forebrain. The basal forebrain contains a mixed population of neurons, some of which are cholinergic. To identify the relative contribution of the noncholinergic neurons to arousal, here we utilized 192-IgG-saporin to lesion the basal forebrain cholinergic neurons and determine whether microinjection of hypocretin-1 to the basal forebrain is still effective in inducing arousal. In Sprague-Dawley rats given 192-IgG-saporin (intraventricular, 6 microg; n=7) 92% of the basal forebrain cholinergic neurons were destroyed compared to nonlesioned rats (n=5). In the lesioned rats microinjection of hypocretin-1 (0.0625, 0.125 or 0.25 nmol in 250 nL) to the basal forebrain increased waking and suppressed sleep (both non-REM and REM) in a concentration-dependent manner and to the same extent as in nonlesioned rats. These results suggest that, in the absence of the basal forebrain cholinergic neurons, the basal forebrain noncholinergic neurons are able to convey hypocretin's arousal signal unabated.

Impact of land disturbance on the fate of arsenical pesticides.

Increasing development of historic farmlands raises questions regarding the fate of pesticides applied when these land were in cultivation. We quantified As and Pb budgets in field soils in two orchards where arsenical pesticides were applied in the early 20th century and a third uncontaminated control field. Sequential extractions and X-ray analyses also were used to determine mineral phases. In addition, we measured metal loads in drainages adjacent to the fields and in two common macroinvertebrate taxa within the wetland at the outlet of the drainages. We find that the applied As and Pb have undergone little vertical redistribution; concentrations of As and Pb in the top 25 cm of contaminated orchard soils are higher than in the uncontaminated control field. However, none of the applied lead arsenate (PbHAsO4) remains in its original mineral phase. Instead, the metals are now primarily adsorbed onto fine silt and clay-sized amorphous oxides and organic matter. Further, physical erosion associated with tilling and replanting appears to have mobilized the fine-particulate-bound As and Pb in one orchard. The remobilized metals are found in sediments in the stream channel draining the tilled orchard. It is unclear if the As and Pb transported sediments are biologically active; average macroinvertebrate metal burdens in the wetland are not elevated above those observed elsewhere in the region. However, little of the mobilized metals may have reached the wetland. These results demonstrate that land use change can significantly impact the retention of arsenical pesticides.

Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes.

In mammals, sleep is regulated by circadian and homeostatic mechanisms. The circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the timing of sleep, whereas homeostatic factors determine the amount of sleep. It is believed that these two processes regulating sleep are independent because sleep amount is unchanged after SCN lesions. However, because such lesions necessarily damage neuronal connectivity, it is preferable to investigate this question in a genetic model that overcomes the confounding influence of circadian rhythmicity. Mice with disruption of both mouse Period genes (mPer)1 and mPer2 have a robust diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity in a free-run condition. Here, we examine the role of the mPer genes on the rhythmic and homeostatic regulation of sleep. In entrained conditions, when averaged over the 24-h period, there were no significant differences in waking, slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1, mPer2, mPer3, mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept awake for 6 h (light period 6-12), and the mPer mutants exhibited increased sleep drive, indicating an intact sleep homeostatic response in the absence of the mPer genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants became arrhythmic, but they continued to maintain their sleep levels even after 36 days in free-running conditions. Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep.

The Mathematics Anxiety Rating Scale, a brief version: psychometric data.

As a measure of mathematics anxiety, the Mathematics Anxiety Rating Scale (MARS) has been a major scale used for research and clinical studies since 1972. Despite the usefulness of the original scale, researchers have sought a shorter version of the scale partly to reduce the administration time of the original 98-item scale. This study created a shorter version of the MARS and provides reliability and validity information for the new version. The Cronbach alpha of .96 indicated high internal consistency, while the test-retest reliability for the MARS 30-item was .90 (p<.001). The validity data confirm that the MARS 30-item test is comparable to the original MARS 98-item scale.