Parameter logP Research Articles

Antidepressants enter cells, organelles, and membranes.

We begin by summarizing several examples of antidepressants whose therapeutic actions begin when they encounter their targets in the cytoplasm or in the lumen of an organelle. These actions contrast with the prevailing view that most neuropharmacological actions begin when drugs engage their therapeutic targets at extracellular binding sites of plasma membrane targets-ion channels, receptors, and transporters. We review the chemical, pharmacokinetic, and pharmacodynamic principles underlying the movements of drugs into subcellular compartments. We note the relationship between protonation-deprotonation events and membrane permeation of antidepressant drugs. The key properties relate to charge and hydrophobicity/lipid solubility, summarized by the parameters LogP, pKa, and LogDpH7.4. The classical metric, volume of distribution (Vd), is unusually large for some antidepressants and has both supracellular and subcellular components. A table gathers structures, LogP, PKa, LogDpH7.4, and Vd data and/or calculations for most antidepressants and antidepressant candidates. The subcellular components, which can now be measured in some cases, are dominated by membrane binding and by trapping in the lumen of acidic organelles. For common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), the target is assumed to be the eponymous reuptake transporter(s), although in fact the compartment of target engagement is unknown. We review special aspects of the pharmacokinetics of ketamine, ketamine metabolites, and other rapidly acting antidepressants (RAADs) including methoxetamine and scopolamine, psychedelics, and neurosteroids. Therefore, the reader can assess properties that markedly affect a drug's ability to enter or cross membranes-and therefore, to interact with target sites that face the cytoplasm, the lumen of organelles, or a membrane. In the current literature, mechanisms involving intracellular targets are termed "location-biased actions" or "inside-out pharmacology". Hopefully, these general terms will eventually acquire additional mechanistic details.

Heterogeneous biocatalytical esterification by recombinant Thermomyces lanuginosus lipase immobilized on macroporous carbon aerogel

Heterogeneous biocatalysts prepared by immobilizing recombinant lipases are promising for implementation in organic synthesis of various esters used as fragrances, emollients, emulsifiers, non-ionic surfactants, plasticizers, etc. For this research, the Thermomyces lanuginosus lipase produced by the authoring recombinant Pichia pastoris strain was adsorbed on the authoring macroporous carbon aerogel. The prepared biocatalysts were studied in the periodic processes of enzymatic esterification carried out in nonconventional anhydrous media of organic solvents at ambient conditions (22 ± 2 °C, 1 bar). Biocatalytical activities depended strongly on both the selected pair of lipase substrates (acid and alcohol) involved in reaction and the organic solvent used for esterification. The reaction rates of fatty C7 acid esterification with double and triple bond C3 alcohols, such as allyl and propargyl alcohols, were found to be 2–4 times lower than with aliphatic propanol. Isomerism of an acid (not alcohol) molecule greatly affected the esterification rates. It was observed that isomers of C4 and C5 acids (iso-butyric and iso-valeric) practically did not react with butanol. The esterification rates strongly depended on the polarity of the organic solvent characterized by the parameter logP. With an increase in the solvent polarity from non-polar hexane to polar acetone, the esterification rate decreased by two orders of magnitude. The prepared lipase-active biocatalysts had a sufficiently high operational stability under the chosen optimal reaction conditions; their stationary activity (300 ± 100 U·g–1) did not change in periodic reaction cycles during several tens of hours.

Phosphine boranes as less hydrophobic building blocks than alkanes and silanes: Structure-property relationship and estrogen-receptor-modulating potency of 4-phosphinophenol derivatives

Increasing structural options in medicinal chemistry is important for the development of novel and distinctive drug candidates. In this study, we focused on phosphorus-containing functionalities. We designed and synthesized a series of phosphinophenol derivatives and determined their physicochemical properties, including hydrophobicity parameter LogP, and their biological activity toward estrogen receptor (ER). Notably, the phosphine borane derivatives (9 and 14) exhibited potent ER-antagonistic activity, exceeding the potency of the corresponding alkane (15) and silane (16) derivatives, despite having a less hydrophobic nature. The determined physicochemical parameters will be helpful for the rational design of phosphorus-containing biologically active compounds. Our results indicate that phosphine boranes are a promising new chemical entry in the range of structural options for drug discovery.

Adsorption of Natural 3-Phenylpropenic Acids on Cerium Dioxide Surface

It has been shown that adsorption of natural antioxidants, such as 3-phenylpropenic (cinnamic), 3-(4-hydroxyphenyl)propenic (coumaric), and 3-(3-methoxy-4-hydroxyphenyl)propenic (ferulic) acids, on the surface of cerium dioxide is characterized by S-type isotherms, while adsorption of 3-(3,4-dihydroxyphenyl)propenic (caffeic) acid is described by an H-type isotherm. A linear correlation between adsorption values and hydrophobicity parameter logP has been found in initial regions of the S-type isotherms, with such correlation being typical for parallel orientation of adsorbed molecules relative to an adsorbent surface. The maximum adsorption values (≈2.9 × 10–4 mol/g), as well as dissociation constants (pKCOOH = 4.4–4.6), are almost identical for all acids, thereby suggesting that adsorbate molecules are predominantly bound to the adsorbent surface via carboxyl groups. The presence of hydroxyl groups in molecules of coumaric, ferulic, and caffeic acids widens the рН range of their adsorption as compared with cinnamic acid and promotes their oxidation on the cerium dioxide surface.

Determination of Acidity Constants, Partition Coefficients between Water and 1-Octanol, and Deprotonation Route of 4-tert-buthyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol and 4-hydroxy-3,5-bis(morpholin-1-ylmethyl)benzonitrile; Compounds with Antihypert

The pKa values for two compounds (LQM303 and LQM314) with antihypertensive properties were determined by UV spectroscopy (T = 310.15 K and I = 0.15 M) and by Capillary Zone Electrophoresis (T = 310.15 K and I = 0.05 M), using the program SQUAD. The partition coefficients (logP) between water and 1-octanol have also been determined experimentally, demonstrating that both compounds fulfill with the physicochemical parameter logP ≤ 5 of Lipinski´s rules. Calculations on the framework of Density Functional Theory have allowed identifying the functional group related to each pKa for each compound.

An alternative approach for the use of water solubility of nonionic pesticides in the modeling of the soil sorption coefficients

The collection of data to study the damage caused by pesticides to the environment and its ecosystems is slowly acquired and costly. Large incentives have been established to encourage research projects aimed at building mathematical models for predicting physical, chemical or biological properties of environmental interest. The organic carbon normalized soil sorption coefficient (Koc) is an important physicochemical property used in environmental risk assessments for compounds released into the environment. Many models for predicting logKoc that have used the parameters logP or logS as descriptors have been published in recent decades. The strong correlation between these properties (logP and logS) prevents them from being used together in multiple linear regressions. Because the sorption of a chemical compound in soil depends on both its water solubility and its water/organic matter partitioning, we assume that models capable of combining these two properties can generate more realistic results. Therefore, the objective of this study was to propose an alternative approach for modeling logKoc, using a simple descriptor of solubility, here designated as the logarithm of solubility corrected by octanol/water partitioning (logSP). Thus, different models were built with this descriptor and with the conventional descriptors logP and logS, alone or associated with other explanatory variables representing easy-to-interpret physicochemical properties. The obtained models were validated according to current recommendations in the literature, and they were compared with other previously published models. The results showed that the use of logSp instead of conventional descriptors led to simple models with greater statistical quality and predictive power than other more complex models found in the literature. Therefore, logSP can be a good alternative to consider for the modeling of logKoc and other properties that relate to both solubility and water/organic matter partitioning.

Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski's rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas.

Effects of substituent and solvent on the UV absorption energy of 4,4′-disubstituted stilbenes

Twenty five samples of 4,4′-disubstituted stilbene derivatives were synthesized, and their UV absorption max wavelengths were determined in over 10 kinds of solvents including cyclohexane, ether, chloroform, acetonitrile and ethanol, in which 242 experimental data were recorded. The effects of substituents and solvents on the energy of their UV absorption max wavelengths were discussed. The research results showed: the energy of UV absorption max wavelengths of 4,4′-disubstituted stilbenes was mainly affected by their intramolecular structure (substituent effect) in a given solvent, that is, the energy is dominated by both of excited-state substituent parameter σ CC ex and polar substituent constant σ p. While their energy was dominated by the substituent effect and solvent effect in different kinds of solvents. An equation quantifying the energy of UV absorption max wavelengths of 4,4′-disubstituted stilbenes was developed. In addition, it is found that the n-octanol/water partition coefficient (logP) is more effective than the solvatochromic dye (E T(30)) in scaling the solvent effect. The equation employed the parameter logP has a better correlation and more specific physical meaning. Further, the energies of UV absorption max wavelengths of some reported compounds were predicted by the obtained equation, which are in agreement with their experimental values.

Analysis and Prediction of Perfluorane Adsorption of Drugs on the Basis of the Physicochemical Properties of Ligands

The relationships between drug affinity constant (Kag) for the particles of perfluorane nanoemulsion and physicochemical properties of ligands were studied by correlation and multiple regression analyses. The following parameters were applied: lipophilicity (LogP), molecular weight (MW), topological polar surface area (TPSA), the number of hydrogen donors (Don) and acceptors (Acc) in the formation of a hydrogen bonds, the number of rotating bonds (Rot), and drug molecule ionization constant (pKa). The Kaf — physicochemical properties relationships were found to be mainly nonlinear and to mostly show up in the lipophilicility parameter LogP of ligands. During the multiple regression analysis, a number of regression equations were derived, which described the relationship of the perfluorane affinity Kaf to the physicochemical properties of drugs and could predict this interaction for both existing and newly synthesized compounds.

Comparison of physicochemical properties and biological activities of opioid morphinans interacting with mu opioid receptors

Morphinans play an important role among therapeutically valuable opioids. They include powerful pain relieving agents such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogues (e.g. levorphanol, butorphanol). These opioid drugs produce their biological actions through three receptor types, μ, δ and κ, belonging to the family of seven transmembrane G protein-coupled receptors. All three opioid receptors are located in the central and peripheral nervous systems of many species including human. Morphine and related opioids currently prescribed as potent analgesics for the treatment of severe pain produce their analgesic activity primarily through their agonist action at μ opioid receptors, which is the main receptor type targeted for pharmacotherapy of pain. Despite their widespread use, opioid drugs have a number of severe side effects including respiratory depression, emesis, sedation, constipation, tolerance, and physical dependence. Consequently, a great deal of effort was spent trying to develop safer, more efficacious and non-addicting compounds, with the goal of an improved therapeutic index. Optimal physicochemical properties are often an important consideration for the development of bioactive molecules as therapeutic agents. Therefore, a significant aim in medicinal chemistry research and drug development is to predict the behavior of targeted molecules based on their physicochemical features. This task, however, cannot be accomplished without correlating and understanding the differences in the physicochemical and pharmacological properties of existing opioid morphinans. Toward this goal, we performed a comparative study on physicochemical properties and biological activities of well-known opioid morphinans such as the naturally occurring alkaloid morphine, and semisynthetic analogues e.g. oxymorphone. Besides the classical and clinically relevant opioid analgesics, synthetic morphinans developed by our group were included in the study, the 14-O-methyl derivative of oxymorphone and its 5-methyl substituted analogue, 14-methoxymetopon. The major physicochemical parameters (pKa, logP and logD) have been experimentally determined using a Sirius PCA200/Cheqsol Instrument. In vitro binding affinities and selectivities to opioid receptors were determined in rodent brain membranes using binding assays. Analgesic potencies were evaluated after subcutaneous administration to mice using tail-flick and hot-plate tests. The structure-activity relationship observations, combining physicochemical and biological data, will be discussed. Altogether, the present study indicate that specific structural elements are required to confer high affinity/selectivity for μ opioid receptors and potent agonist and analgesic activity in the morphinan class of opioids, and are important in drug development.

Structure-activity study of phosphoramido acid esters as acetylcholinesterasf inhibitors

Phosphoramido acid esters (CH3)2NP(O)X(p-OC6H4-CH3) (containing P-Cl (1), P-O (2), P-F (3), P-CN (5), and P-N (4,6) bonds, X for 2, 4 and 6 is OCH3, (C2H5)2N and morpholin) have been synthesized to investigate the structure-activity study of AChE enzyme inhibition, through the parameters logP, δ31P and IC50. After their characterization by 31P, 31P{1H}, 13C, 1H NMR, IR and mass spectroscopy, the parameters logP and δ31P (31P chemical shift in NMR) were used to evaluated the lipophilicity and electronical properties. The ability of compounds to inhibit human AChE was predicted by PASS software (version 1.193), and experimentally evaluated by a modified Ellman's assay.

Determination of the Lipophilicity Parameters R M0 and LogP of New Azaphenothiazines by Reversed‐Phase Thin‐Layer Chromatography†

The lipophilicity parameters (R M0 and logP TLC) of three types of azaphenothiazines 1–3 were determined by reversed‐phase thin‐layer chromatography on RP‐18 silica plates with acetone‐aqueous TRIS (tris(hydroxymethyl)aminomethane) buffer as the mobile phase. The R M values were linearly dependent on the concentration of acetone, and extrapolated to 0% of acetone, gave the lipophilicity parameter R M0. The parameter R M0 and specific hydrophobic surface area b were significantly intercorrelated showing a congeneric class of azaphenothiazines 1–3. The parameter logP TLC was determined from the R M0 values by use of a calibration curve obtained for five standards. The determined parameters were discussed in the terms of structure lipophilicity relationships and compared with data obtained from seven calculation programs.

Development of a Neural Network Simulator for Structure-activity Correlation of Molecules: Neco (7)- Hydrophobic Parameter (logP) Prediction of Perillartine Derivatives -

学習方法として中間層において自己組織化を行い、全体に教師付学習の両方を行う、自己組織化とパーセプトロンを融合した二ューラルネットワークシミュレータの開発をプラットフォーム非依存性を持つ Java 言語を用いて行った。本シミュレータは、自己組織化と教師付学習の双方の特徴を併せもつため、従来のニューラルネットワークよりも高精度な認識処理を実現し、かつ高速学習が可能となる。 このシミュレータを用いて、分子構造によって甘味や苦味の性質を示す22種類のペリラルチン類の疎水性パラメータ logP の予測を行った。入力パラメータは分子構造STERIMOLパラメータ5種のパラメータと甘味／苦味の分類値を用いた。出力層のノード数を１つにすることで、 logP の値を連続した数値データとして予測できるようにした。絶対誤差が平均して0.02までの学習を500回程度で行うことができ、また未学習データに対しては平均して0.3程度の絶対誤差、最大でも0.8程度の絶対誤差で予測が可能であった。単純パーセプトロンの予測精度は、平均して0.6程度の絶対誤差であり、また最大の絶対誤差は1.3程度と大きく、本手法がより精度の高い予測を行っていることがわかった。n 本手法は学習回数が単純パーセプトロンに比較して1/5 - 1/10程度少なく、高速学習が可能であった。

The Energy Aspects of Oil/Water Partition. Proposition of Novel Hydrophobia Parameters for the Treatment of Quantitative Structure-Activity Relationships

Abstract Conventional hydrophobia parameter logP, decimal logarithm of partition coefficient, has been separated into the corresponding terms of enthalpy and entropy. These novel terms are determined for various alcohols and benzoic acids, and shown to give promising results in the analysis of quantitative structure-activity relationships.

A non-linear function for the approximation of octanol/water partition coefficients of aromatic compounds with multiple chlorine substitution

From the comparison of linear and power curve regression analyses of several sets of congeners, it is suggested that the increasing chlorine substitution of aromatic and heterocyclic parent compounds, such as benzene, aniline, pyridine, and diphenyl results in declining increases of the octanol/water partition coefficients. The partition coefficients of the chloro congeners follow the general equation logP N = (N +1)∗ logP O , where N is the number of chlorine substituents, logP O the partition coefficient of the parent compound and b is a constant, specific for each set of congeners. The parameters logP O and b are also correlated with each other by the equation b = z∗ logP O Y , where z and y are the same constants for all sets. Together, the two equations allow the quick estimation of the partition coefficient of any congener from the known value of another. This ability is of special importance for compounds with 4 < logP, where experimental values are difficult to obtain.