AR 231453

AR 231453 is an agonist of GPR119 with EC50 value of 0.68nM [1].

AR 231453 is the first subnanomolar agonist of GPR119. It is highly selective against GPR119 over a 76 receptor and enzyme profiling panel (CEREP) including the known incretin receptors. It also has no activity to 140 known and orphan GPCRs in melanophore dispersion assays. Besides that, AR 231453 is reported to stimulate cAMP production via endogenously expressed GPR119 in HIT-T15 cell line with EC50 value of 4.7nM [1].

In vivo assay shows that AR 231453 has activity in rodents. It can enhance glucose-dependent insulin release and improve oral glucose tolerance in wild-type C57/bl6J mice but not in GPR119-deficient mice at a dose of 20 mg/kg. Due to its activity to active GPR119, AR 231453 is expected to be a potent anti-diabetic agent [1].

References:
[1] Semple G, Fioravanti B, Pereira G, Calderon I, Uy J, Choi K, Xiong Y, Ren A, Morgan M, Dave V, Thomsen W, Unett DJ, Xing C, Bossie S, Carroll C, Chu ZL, Grottick AJ, Hauser EK, Leonard J, Jones RM. Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J Med Chem. 2008 Sep 11;51(17):5172-5.

Theoretical Cross Sections of the Inelastic Fine Structure Transition M((2)P1/2) + Ng <--> M((2)P3/2) + Ng for M = K, Rb, and Cs and Ng = He, Ne, and Ar.[Pubmed:28368614]

J Phys Chem A. 2017 May 11;121(18):3340-3351.

Scattering matrix elements of the inelastic fine structure transition M((2)P1/2) + Ng <--> M((2)P3/2) + Ng are computed using the channel packet method (CPM) for alkali-metal atoms M = K, Rb, and Cs, as they collide with noble-gas atoms Ng = He, Ne, and Ar. The calculations are performed within the block Born-Oppenheimer approximation where excited state VA(2)Pi1/2(R), VA(2)Pi3/2(R), and VB(2)Sigma1/2(R) adiabatic potential energy surfaces are used together with a Hund's case (c) basis to construct a 6 x 6 diabatic representation of the electronic Hamiltonian. Matrix elements of the angular kinetic energy of the nuclei incorporate Coriolis coupling and, together with the diabatic representation of the electronic Hamiltonian, yield a 6 x 6 effective potential energy matrix. This matrix is diagonal in the asymptotic limit of large internuclear separation with eigenvalues that correlate to the (2)Pj alkali atomic energy levels. Scattering matrix elements are computed using the CPM by preparing reactant and product wave packets on the effective potential energy surfaces that correspond to the excited (2)Pj alkali states of interest. The reactant wave packet is then propagated forward in time using the split operator method together with a unitary transformation between the adiabatic and diabatic representations. The Fourier transformation of the correlation function between the evolving reactant wave packet and stationary product wave packet yields state-to-state scattering matrix elements as a function of energy for a particular choice of total angular momentum J. Calculations are performed for energies that range from 0.0 to 0.01 hartree and values of J that start with a minimum of J = 0.5 for all M + Ng pairs up to a maximum that ranges from J = 450.5 for KAr to J = 100.5 for CsAr. A sum over J together with an average over energy is used to compute thermally averaged cross sections for a temperature range of T = 0-400 K.

Simulation of carbon nanotube welding through Ar bombardment.[Pubmed:28365822]

J Mol Model. 2017 Apr;23(4):148.

Single-walled carbon nanotubes show promise as nanoscale transistors for nanocomputing applications. This use will require appropriate methods for creating electrical connections between distinct nanotubes, analogous to welding of metallic wires at larger length scales, but methods for performing nanoscale chemical welding are not yet sufficiently understood. This study examines the effect of Ar bombardment on the junction of two crossed single-walled carbon nanotubes, to understand the value and limitations of this method for generating connections between nanotubes. A geometric criterion was used to assess the quality of the junctions formed, with the goal of identifying the most productive conditions for experimental ion bombardment. In particular, the effects of nanotube chirality, Ar impact kinetic energy, impact particle flux and fluence, and annealing temperature were considered. The most productive bombardment conditions, leading to the most crosslinking of the tubes with the smallest loss of graphitic (i.e., conductive) character, were found to be at relatively mild impact energies (100 eV), with low flux and high-temperature (3000 K) annealing. Particularly noteworthy for experimental application, a high junction quality is maintained for a relatively broad range of fluences, from 3 x 10(19) m(-2) to at least 1 x 10(20) m(-2).

Lack of beta2-AR Increases Anxiety-Like Behaviors and Rewarding Properties of Cocaine.[Pubmed:28348522]

Front Behav Neurosci. 2017 Mar 13;11:49.

It is well known that beta-adrenoceptors (beta-ARs) play a critical role in emotional arousal and stressful events, but the specific contributions of the beta2-AR subtype to the psychological disorders are largely unknown. To investigate whether beta2-AR are involved in anxiety-like behavior and reward to addictive drugs, we conducted a series of behavioral tests on beta2-AR knock-out (KO) mice. beta2-AR KO mice exhibited increased preference for the dark compartment and closed arm in tests of Light/Dark box and elevated plus maze, indicating that beta2-AR deletion elevates level of anxiety or innate fear. beta2-AR KO mice also showed decreased immobility in tail suspension test (TST), suggesting that beta2-AR deletion inhibits depression-like behavior. Interestingly, beta2-AR ablation did not change basal locomotion but significantly increased locomotor activity induced by acute cocaine administration. beta2-AR KO mice showed enhanced place preference for cocaine, which could be attenuated by beta1-selective AR antagonist betaxolol. Consistently, beta2-AR agonist suppressed cocaine-conditioned place preference (CPP). These data indicate that beta2-AR deletion enhances acute response and reward to cocaine. Our results suggest that beta2-AR regulates anxiety level, depression-like behavior and hedonic properties of cocaine, implicating that beta2-AR are the potential targets for the treatment of emotional disorders and cocaine addiction.

Explained Variance and Intraclass Correlation in a Two-Level AR(1) Model.[Pubmed:28375685]

Multivariate Behav Res. 2017 Jul-Aug;52(4):403-415.

The total variance of a first-order autoregressive AR(1) time series is well known in time series literature. However, despite the increased use and interest in two-level AR(1) models, an equation for the total variance of these models does not exist. This paper presents an approximation of this total variance. It will be used to compute the unexplained and explained variance at each level of the model, the proportion of explained variance, and the intraclass correlation (ICC). The use of these variances and the ICC will be illustrated using an example concerning structured diary data about the positive affect of 96 married women.