Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the α6 subtype

Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure–activity relationship are discussed in the context of the design of small molecules targeting smoking cessation

Structural differences determine the relative selectivity of nicotinic compounds for native α4β2^*-, α6β2^*-, α3β4^*- and α7-nicotine acetylcholine receptors

Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, α4β2^* and α6β2^*-nAChR have the highest affinity for nicotine (where ^* indicates possibility of other subunits). The α4β2^*-nAChRs are widely distributed, while α6β2^*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. α4β2^*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics.We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compoundswere screened usingmembrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing hα7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, α4β2^*, α6β2^*, α7 and α3β4^*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at α4b2^* and α6β2^*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for α6β2^*-nAChR

3D Printed Alternative to the Standard Synthetic Flocked Nasopharyngeal Swabs Used for COVID-19 testing.

BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, can be detected in respiratory samples by Real-time Reverse Transcriptase (RT)-PCR or other molecular methods. Accessibility of diagnostic testing for COVID-19 has been limited by intermittent shortages of supplies required for testing, including flocked nasopharyngeal (FLNP) swabs. METHODS:We developed a 3D-printed nasopharyngeal (3DP) swab as a replacement of the FLNP swab. The performance of 3DP and FLNP swabs were compared in a clinical trial of symptomatic patients at three clinical sites (n=291) using three SARS-CoV-2 EUA tests: a modified version of the CDC Real-time Reverse Transcriptase (RT)-PCR Diagnostic Panel and two commercial automated formats, Roche Cobas and NeuMoDx. RESULTS:The cycle threshold (C(t)) values from the gene targets and the RNase P gene control in the CDC assay showed no significant differences between swabs for both gene targets (p=0.152 and p=0.092), with the RNase P target performing significantly better in the 3DP swabs (p & 0.001). The C(t) values showed no significant differences between swabs for both viral gene targets in the Roche cobas assay (p=0.05 and p=0.05) as well as the NeuMoDx assay (p=0.401 and p=0.484). The overall clinical correlation of COVID-19 diagnosis between all methods was 95.88% (Kappa 0.901). CONCLUSIONS:3DP swabs were equivalent to standard FLNP in three testing platforms for SARS-CoV-2. Given the need for widespread testing, 3DP swabs printed on-site are an alternate to FLNP that can rapidly scale in response to acute needs when supply chain disruptions affect availability of collection kits

Structure-Activity Studies Of 7-Heteroaryl-3-Azabicyclo[3.3.1]Non-6-Enes: A Novel Class Of Highly Potent Nicotinic Receptor Ligands

The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes. © 2012 American Chemical Society

Immersive Projection Technology. Benefits for the industry

The use of Virtual Reality in industry is connected with high expectations. To meet these expectations, the different tasks transferred to VR systems had to be chosen with respect to the different characteristics of the Immersive Projection Technology (IPT) systems. The needs and reasons for using VR and especially the task-specific requirements that favor IPT systems and their characteristics will be discussed in this paper. Some examples of VR-applications based on IPT systems describe the present state of research at the Fraunhofer IAO

Influence of different visualization techniques of 3D free-form surfaces on perceptual performance in a CAVE

Computer-aided design methods are extensively applied in the design of aircraft, automobiles, buildings, computer and many other products. In the next future, CAD methods will be employed in conjunction with 3D immersive displays, which may dramatically improve the possibilities of visualization and interaction offered by common 2D display CAD workstations. Thus, careful evaluation needs to be made as to how the computer-generated object is represented on 3D display. It is commonly recognized that a computer-generated 3D object should be a) an accurate description of the model being designed b) presented in a realistic and integrated format, so that it can be visualized and interpreted without introducting uncertainty regarding to the represented proprieties (Brown, 1995). To ensure that the displayed 3D image will satisfy these requirements, it is important focusing on which perceptual/cognitive operation is performed by the user during the design process. We performed one experiment to examine the effects of different visualization techniques of 3D computer-generated free-form surfaces on depth perception, using Steven's stimulus magnitude estimation paradigm. The factors we investigated were presence versus absence of binocular disparity, four different monocular coding techniques (wireframe, flat shading, Gouraud shading, Gouraud shading and normals) and two levels of shape complexity. We found that a stereoscopic image provides subjects with a visual cue that not only enhances perceived relief of 3D forms but also improves accuracy of activities necessary for 3D design, such as depth estimation of free-form surfaces. Furthermore, the nature of the experimental task implies that stereoscopic displays can be most useful when information is presented from a vertical viewpoint