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Log D (log + d)
Selected AbstractsIntroduction of lipidization,cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activitiesJOURNAL OF PEPTIDE SCIENCE, Issue 9 2010Brad R. Green Abstract The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization,cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization,cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular musclesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2004Popat N. Patil There are two distinct kinetic functional pharmacological procedures by which the equilibrium affinity constant, KB, of a competitive reversible blocker is obtained. The classical method on an organ system requires the study of the parallel displacement of the agonist concentration-response curve in the presence of the blocker. In the second method, the agonist-evoked functional mechanical response is reduced to half by the blocker IC50 (the concentration required for 50% inhibition). In relation to these parameters the role of the ionization constant pKa and liposolubility log Pc or log D of blockers was examined. On the ciliary muscle from human eye, IC50/KB ratios for (±)-atropine, its quaternary analogue (±)-methylatropine, (-)-scopolamine, (±)-cyclopentolate, (-)-tropicamide, (±)-oxybutynin and pirenzepine were 15, 23, 4.4, 2.6, 1.66, 1.46 and 1.71, respectively. The ratios on the iris sphincter were comparable with those of ciliary muscle. When compared with large proportions of ionized molecules with water soluble properties of (±)-atropine and (±)-methylatropine, relatively high amounts of un-ionized and/or with greater partitioning of all other blockers in the lipoid barrier co-related well to low IC50/KB ratios, as predicted by the classical theory of competitive drug antagonism. It was hypothesized that due to receptor biophase access, the reduction of the mechanical response of the agonist by the highly ionized water-soluble antagonist at IC50 represented time-distorted "pseudo-equilibrium" estimation, where a higher concentration of the blocker was needed. On the other cholinergic effectors, like that of rat anococcygeus muscle or frog rectus abdominus muscle, IC50/KB ratios of respective blockers atropine or (+)-tubocurarine and hexamethonium were close to 1. Thus physicochemical properties, which affect the distribution coefficient log D and the tissue morphology (where asymmetric distribution of receptors may occur), appeared to be a critical factor in the analysis of the affinity parameters of the competitive reversible blocker. On the intraocular muscles, two functional pharmacological procedures for obtaining KB and IC50 values were not kinetically equivalent. [source] Structure-Activity Relationships for the Toxicity of Substituted Poly-hydroxylated Benzenes to Tetrahymena pyriformis: Influence of Free Radical FormationMOLECULAR INFORMATICS, Issue 6 2003Tatiana Abstract The aim of this study was to develop quantitative structure-activity relationships for the toxicity to Tetrahymena pyriformis of 30 substituted poly-hydroxylated benzenes. Physico-chemical descriptors for the expression of free radical formation, associated with the OH moiety on the aromatic ring, were calculated. These included one-electron equilibrium constants that did and did not account for the oxidation of an OH-group, homolytic bond dissociation energy (BDE), electronegativity (EN) and absolute hardness (AH), in addition to the distribution coefficient (log D) as a measure of hydrophobicity. The reactivity descriptors were calculated using the semi-empirical AM1 Hamiltonian in the MOPAC molecular orbital software. Statistically significant two-parameter QSARs for toxicity were obtained by combination of log D with either BDE or AH. The QSARs suggested that toxicity is associated with hydrophobicity and the probability of radical formation. [source] Prediction of human blood-to-plasma drug concentration ratioBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5-6 2010Takahide Uchimura Abstract The objective of this study was to predict Rb (blood/plasma ratio) in humans using a simple method. Human and rat Rb and free fraction in plasma (fp) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (Kb) was calculated using fp and Rb. Four methods were used for the prediction of Rb: (A) use of rat Rb; (B) use of Rb calculated from rat Kb and human fp; (C) correlation of human log ((1,fp)/fp) and human log Kb; and (D) correlation of log D with human log Kb. The Rb of 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human log Kb, human log ((1,fp)/fp), and log D; however, no obvious correlation was observed among human Rb, human log ((1,fp)/fp), and log D. The errors within 1.25-fold for methods A,D were 68.3%, 77.6%, 61.5% and 64.8%, respectively. All predictive methods considered here were superior to the use of the average value of human Rb or Rb=1. Rat Rb corrected by human fp improved the accuracy of the prediction. Method B was the most accurate of the four methods. Copyright © 2010 John Wiley & Sons, Ltd. [source] On the complexity of Rocchio's similarity-based relevance feedback algorithmJOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY, Issue 10 2007Zhixiang Chen Rocchio's similarity-based relevance feedback algorithm, one of the most important query reformation methods in information retrieval, is essentially an adaptive learning algorithm from examples in searching for documents represented by a linear classifier. Despite its popularity in various applications, there is little rigorous analysis of its learning complexity in literature. In this article, the authors prove for the first time that the learning complexity of Rocchio's algorithm is O(d + d2(log d + log n)) over the discretized vector space {0,,, n , 1}d, when the inner product similarity measure is used. The upper bound on the learning complexity for searching for documents represented by a monotone linear classifier over {0,,, n , 1}d can be improved to, at most, 1 + 2k (n , 1) (log d , log(n , 1)), where k is the number of nonzero components in q. Several lower bounds on the learning complexity are also obtained for Rocchio's algorithm. For example, the authors prove that Rocchio's algorithm has a lower bound on its learning complexity over the Boolean vector space {0, 1}d. [source] The fractional congestion bound for efficient edge disjoint routingNETWORKS: AN INTERNATIONAL JOURNAL, Issue 3 2008Alok Baveja Abstract This article investigates the following problem: Given the fractional relaxation of the edge disjoint routing problem, how small a fractional congestion is sufficient to guarantee efficient edge disjoint routing? That is, what is the largest possible value v such that a fractional flow with congestion at most v, can be efficiently converted into an edge disjoint routing? Leighton, Lu, Rao, and Srinivasan (SIAM J Comput 2001) have established that fractional congestion of at most the order of O(1/(d log k)) is sufficient, where d is the maximum path length in the fractional relaxation, and k is the number of pairs to be routed. It is also known that ,(1/d) is the correct bound, if we are only interested in an existence result (Leighton, Rao, and Srinivasan, Hawaii International Conference on System Sciences, 1998). Motivated by the fact that d is small for many types of routing problems, specifically, polylogarithmic for expander graphs, this article improves upon the former result by showing O(1/(d log d)) fractional congestion to suffice. © 2007 Wiley Periodicals, Inc. NETWORKS, 2008 [source] | |||||||||||||