The geometry and flow of Fireweed Rock Glacier, Alaska

Thesis (M.S.) University of Alaska Fairbanks, 2002Little is known about the geometry, internal structure or flow of rock glaciers. Geophysical investigations were carried out on Fireweed Rock Glacier to define its geometry. Transient electromagnetic (TEM) methods were effective in determining its shape and depth as well as re-enforcing results of radar and seismic. All of these methods suggest a discontinuity at 15 to 30 m depth. The geometry acquired from these geophysical surveys was used to investigate the motion of the rock glacier. Analysis indicates that motion is concentrated in a pseudo-rectangular subsection of the larger valley on a 'shear plane' at about 27 m depth. We infer that both deformation above and 'sliding' along this shear plane contribute to the observed surface motion. This rock glacier flows relatively quickly for a rock glacier, and has seasonal and annual variations in speed. Some of the variations are related to the quasi-periodic calving at the terminus

Idalopirdine : a small molecule antagonist of 5-HT_6 with therapeutic potential against obesity

5HT(6) receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(−1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer’s disease and schizophrenia. It is a 5HT(6) receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction

The use of machine learning-based sequential virtual screening in the search of new ligands of 5-HT6 receptor

5-HT6 receptor takes part in learning and memory processes. For this reason, the use of ligands of this receptor in the treatment of neurodegenerative diseases such as Alzheimer's disease, depression or autism is being investigated. The development of machine learning (ML) and access to large compound databases allow for the increasing use of these methods in search of new drugs. The use of ML in pre-clinical tests allows for a reduction in time and costs of drug discovery. In this study, we used a sequential virtual screening approach in search of new structures with potential high affinity for the 5-HT6 receptor. Data from the ChEMBL database containing ligand binding affinities, measured as an inhibition constant (Ki), was used as the training dataset. Each step of the screening was based on machine learning models, the task of which was to classify compounds as potentially active and inactive. The first step included a ligand-based drug discovery (LBDD) approach, in which, using Klekota-Roth fingerprints and descriptors describing the chemical structure of the ligands, a classification model was developed to select a preliminary group of candidates from the Otava chemical compound database. In the second step, a structure-based drug discovery (SBDD) approach was used. For this purpose, compounds were docked to the homology model of the 5-HT6 receptor, developed using the AlphaFold algorithm and optimized by Induced-Fit Docking tool and molecular dynamics. Docking poses were scored by a trained Extra Trees classifier. Interactions of a reference ligand with 14 binding site residues were used as features for the trained model. The use of machine learning as a scoring function allowed to improve the virtual screening parameters compared to the Glide GScore scoring function. Based on the obtained model, it was also confirmed that the location of a ligand near the Ser5.43 and Phe5.38 residues is important for binding the compound to the receptor. The procedure has allowed to select 20 candidates with new chemical structures compared to known ligands. In addition, the obtained compounds had a relatively low basic pKa compared to known ligands and thus may be suspected to have a low affinity for hERG channels and good brain penetration

Evaluation of antiplatelet activity of novel guanidine derivatives in the aspects of their adrenergic receptor activity

Designed acetamide derivatives based on guanidine and various heteroaryl carboxylic acids, were preliminary in vitro study of their adrenergic receptor affinity and anti-plateled effects. The obtained results have showed that exchange of 2,6-dichloro-phenyl substituent of guanidine into heteroaryl moieties, caused the decrease of receptor affinity, especially for α1-adrenoceptors. The observed receptor profile of activity for α2BAR was not changed compared to α1-ARs. Moreover, the observed effects on platelet aggregation induced by sub-threshold concentration of collagen and adrenaline strongly suggested that antiaggregant effect of N- (diaminomethylene)-2-(pyridin-3-yl)acetamide and N-(diaminomethylene)-2-(pyridin-4-yl)acetamide depends on their α2B-ARs antagonistic activity

Bucki (2006), Rapid erosion of soft sediments by tidewater glacier advance: Taku Glacier

[1] Taku Glacier in southeast Alaska has advanced 7.5 km over the last 115 years, overriding its own glaciomarine and outwash sediments. We have documented rapid erosion of these sediments by comparing radio echo soundings (RES) along five transects (2003)(2004)(2005) to earlier RES surveys (1989 and 1994) and to early bathymetric surveys of the proglacial fjord. Erosion rates, _ E, reached 3.9 ± 0.8 m

New spirohydantoin derivatives : synthesis, pharmacological evaluation and molecular modeling study

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1í-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HT1A, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic α1 receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT1A/7, was also analyzed in computationa studies. Moreover, two highly selective (9 and 11) 5-HT2A receptor antagonists were obtained

Impact of N-alkylamino substituents on serotonin receptor (5-HTR) affinity and phosphodiesterase 10A (PDE10A) inhibition of isoindole-1,3-dione derivatives

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated