Relationship between Lipophilic Character and Anesthetic Activity

Glave, W. R.; Hansch, Corwin

doi:10.1002/jps.2600610420

Cited by 65 publications

(23 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Years later, in 1958, the influence of the addition of polar and nonpolar groups to arylboronic acids described partitioning between benzene and water as a prognosticator of a compound's BBB permeability 200. A landmark series of studies, starting in the late 1960s, by Corwin Hansch, the pioneer of Quantitative Structure‐Activity Relationships, demonstrated experimentally a parabolic relationship between log P and CNS‐activity in rodents and set the stage for the modern era 201, 202. Hansch, in attempting to quantify the role of lipophilicity, argued that compounds with low log P values favor CNS exclusion and, conversely, within homologous series, optimal CNS penetration occurred with compounds possessing a log P around 2 198, 203.…”

Section: In Silico Models For Blood–brain Barrier Permeability: Predimentioning

confidence: 99%

In vivo, in vitro and in silico methods for small molecule transfer across the BBB

Mensch

Oyarzábal

Mackie

et al. 2009

Journal of Pharmaceutical Sciences

137

125

View full text Add to dashboard Cite

Section: In Silico Models For Blood–brain Barrier Permeability: Predimentioning

confidence: 99%

In vivo, in vitro and in silico methods for small molecule transfer across the BBB

Mensch

Oyarzábal

Mackie

et al. 2009

Journal of Pharmaceutical Sciences

137

125

View full text Add to dashboard Cite

“…Some of the earliest attempts sought to discover relationships between brain penetration (usually determined as log BB) and partition coefficients measured in various solvent systems. For instance, it was suggested in the early 1970s that the optimum log P oct value for diffusion into the CNS was around 2 (Glave and Hansch, 1972;Levin, 1980). In something of a seminal paper, Young et al (1988) at Smith Kline & French Laboratories discovered a linear relationship between log BB and ⌬ log P (ϭ log P oct Ϫ log P cyc ) for 20 histamine H 2 receptor antagonists.…”

Section: A Bit Of Historymentioning

confidence: 99%

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Goodwin¹,

Clark²

2005

J Pharmacol Exp Ther

107

View full text Add to dashboard Cite

Within drug discovery, it is desirable to determine whether a compound will penetrate and distribute within the central nervous system (CNS) with the requisite pharmacokinetic and pharmacodynamic performance required for a CNS target or if it will be excluded from the CNS, wherein potential toxicities would mitigate its applicability. A variety of in vivo and in vitro methods for assessing CNS penetration have therefore been developed and applied to advancing drug candidates with the desired properties. In silico methods to predict CNS penetration from chemical structures have been developed to address virtual screening and prospective design. In silico predictive methods are impacted by the quality, quantity, sources, and generation of the measured data available for model development. Key considerations for predictions of CNS penetration include the comparison of local (in chemistry space) versus global (more structurally diverse) models and where in the drug discovery process such models may be best deployed. Preference should also be given to in vitro and in vivo measurements of greater mechanistic clarity that better support the development of structure-property relationships. Although there are numerous statistical methods that have been brought to bear on the prediction of CNS penetration, a greater concern is that such models are appropriate for the quality of measured data available and are statistically validated. In addition, the assessment of prediction uncertainty and relevance of predictive models to structures of interest are critical. This article will address these key considerations for the development and application of in silico methods in drug discovery.The main interfaces between the central nervous system (CNS) and the peripheral circulation are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The surface area of the former (approximately 20 m 2 ) is several thousand times larger than the latter; thus, the BBB represents the most important barrier between the CNS and the systemic circulation (Pardridge, 2002;Graff and Pollack, 2004). There are at least two aspects of the BBB that make it a formidable barrier to candidate CNS drugs. First, in terms of its morphology, the endothelial cells of which the BBB is composed are connected by complex tight junctions, which severely limit any paracellular transport. Furthermore, a minimal level of pinocytosis and lack of significant membrane fenestrae affords an additional hindrance to the transport of hydrophilic molecules. Second, the BBB includes an array of metabolic enzyme systems and efflux transporters that constitutes a biochemical barrier to the majority of xenobiotics (de Boer et al., 2003). This combination of physical and biochemical barriers establishes the BBB endothelium as quite distinct from other endothelia, and it has been estimated to prevent the brain uptake of more than 98% of potential neurotherapeutics (Pardridge, 2002).

show abstract

“…In all three of the homologous series, the biological effects of the congeners showed parabolic relationships with the independant variable, regardless if this was increasing lipophilicity or increasing molecular weight. This must be anticipated since in the homologous series there is a constant stepwise increase of the molecular weight as well as of the logP values, calculated on the basis that every increase in chain length by one methylene group means an increase of lopP by 0.5 (GLAVE & HANSCH 1972).…”

Section: Discussionmentioning

confidence: 99%

Parabolic Relationship between Lipophilicity and Biological Activity of Aliphatic Hydrocarbons, Ethers and Ketones after Intravenous Injections of Emulsion Formulations into Mice

Jeppsson

1975

Acta Pharmacologica et Toxicologica

View full text Add to dashboard Cite

The relationship between lipophilicity and isoeffective doses of aliphatic hydrocarbons, ethers and ketones has been determined after intravenous injections into mice. Because of the low water solubility of these pharmacons they were injected by using a lipid emulsion formulation of low toxicity. The pharmacological parameters determined were: dose necessary for loss of righting reflex (“AD100”) and highest tolerated amounts (“LD100”) after continous infusion at a constant speed and acute toxicity in 50 % of the animals (LD50) after bolus injection. It was concluded that the relationship between lipophilic character (logP) and isoeffective dose (log 1/C) was satisfied by the general equation log 1/C = a (log P)2 + b (log P) + c for all three groups of pharmacons and thus followed a parabolic pattern.

show abstract

Relationship between Lipophilic Character and Anesthetic Activity

Cited by 65 publications

References 11 publications

In vivo, in vitro and in silico methods for small molecule transfer across the BBB

In vivo, in vitro and in silico methods for small molecule transfer across the BBB

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Parabolic Relationship between Lipophilicity and Biological Activity of Aliphatic Hydrocarbons, Ethers and Ketones after Intravenous Injections of Emulsion Formulations into Mice

Contact Info

Product

Resources

About