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581.
Yazan J. Meqbil Hongyu Su Robert J. Cassell Kendall L. Mores Anna M. Gutridge Benjamin R. Cummins Lan Chen Richard M. van Rijn 《Molecules (Basel, Switzerland)》2021,26(23)
The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment. Here, we screened a relatively small (5120 molecules) physical drug library to identify δOR agonists that underrecruit β-arrestin, as it has been suggested that compounds that efficaciously recruit β-arrestin are proconvulsant. The screen identified a hit compound and further characterization using cellular binding and signaling assays revealed that this molecule (R995045, compound 1) exhibited ten-fold selectivity over µ- and κ-opioid receptors. Compound 1 represents a novel chemotype at the δOR. A subsequent characterization of fourteen analogs of compound 1, however did not identify a more potent δOR agonist. Computational modeling and in vitro characterization of compound 1 in the presence of the endogenous agonist leu-enkephalin suggest compound 1 may also bind allosterically and negatively modulate the potency of Leu-enkephalin to inhibit cAMP, acting as a ‘NAM-agonist’ in this assay. The potential physiological utility of such a class of compounds will need to be assessed in future in vivo assays. 相似文献
582.
Johan Waldn 《Numerical Methods for Partial Differential Equations》1999,15(4):503-520
We study differential equations with singular source terms. For such equations classical convergence results do not apply, as these rely on the regularity of the solution and the source terms. We study some elliptic and parabolic problems numerically and theoretically, and show that, with the right approximation of the singular source terms, full convergence order can be achieved away from the singularities, whereas the convergence will be poor in a vicinity of these. © 1999 John Wiley & Sons, Inc. Numer Methods Partial Differential Eq 15: 503–520, 1999 相似文献
583.
We consider the equivalence classes of graphs induced by the unsigned versions of the Reidemeister moves on knot diagrams. Any graph that is reducible by some finite sequence of these moves, to a graph with no edges, is called a knot graph. We show that the class of knot graphs strictly contains the set of delta‐wye graphs. We prove that the dimension of the intersection of the cycle and cocycle spaces is an effective numerical invariant of these classes. © 2000 John Wiley & Sons, Inc. J Graph Theory 34: 100–111, 2000 相似文献
584.
In this paper a stochastic innovation diffusion model is proposed derived by introducing stochasticity into the well-known Bass model. The stochastic model is solved analytically by using the theory of reducible stochastic differential equations and the first moment of the resulting stochastic process is presented. The parameter estimators of the model are derived by using a procedure which provides the maximum likelihood estimators (MLE) using time series data. Finally, the model is applied to the data of electricity consumption in Greece. Using a simulation technique, it is possible to predict the performance of the consumption process by defining a subdomain to which all possible trajectories of the process should belong with a predefined probability. © 1997 by John Wiley & Sons, Ltd. 相似文献
585.
当样本X1,…,Xn,…,是α-混合时,建立了三角数组的重对数律和Rosenblatt-Parzen核估计的重对数律。 相似文献
586.
双指数分布位置参数的经验Bayes估计问题 总被引:2,自引:0,他引:2
本文在平方损失下导出了双指数分布位置参数的Bayes估计,利用非参数方法构造了位置参数的经验Bayes(EB)估计.在适当的条件下,获得了EB估计的收敛速度.最后,给出了一个例子说明适合定理条件的先验分布是存在的. 相似文献
587.
A recent study on the Taylor series method of second order and the trapezoidal rule for dynamic equations on time scales has been continued by introducing a derivation of the Taylor series method of arbitrary order on time scales. The error and convergence analysis of the method is also obtained. The 2-step Adams–Bashforth method for dynamic equations on time scales is concluded and applied to examples of initial value problems for nonlinear dynamic equations. Numerical results are presented and discussed. 相似文献