- All neutral lipid-soluble substances have depressant (anesthetic) properties.
- This activity is most pronounced in lipid-rich cells, such as neurons.
- The effect increases with increasing partition coefficient, regardless of the structure
of the substance.
Many molecules have such properties and thus exhibit anesthetic effects. Although the
absolute drug concentration necessary to achieve anesthesia varies greatly, the drug
concentration in the lipid phase—that is, in the cell membrane—is within one order of
magnitude, or 20–50 mM, for all anesthetic agents.
In 1954, Mullins, in a modification to the Overton hypothesis, proposed that besides
the membrane concentration of the anesthetic, its volume, expressed as its volume frac-
tion (mole fraction×partial molal volume), is important. This reasoning implied that
the anesthetic, due to its solubility properties, expands the cell membrane, and that
anesthesia occurs when a critical expansion value is reached, at about 0.3–0.5% of the
original volume.
The notion that general anesthesia was solely a property of molecule lipid solubility
persisted into the 1990s. Until that time, it was felt that a high value of logP (logarithm
of the octanol–water partition coefficient) would enable molecules somehow to affect
neuronal membrane structure (“influencing membrane fluidity and function”), thereby
inducing anesthesia. However, by the mid 1990s it was realized that this time-honored
notion of how general anesthetics worked was probably incorrect. It is now appreciated
that they work by binding to the GABA-A receptor in the brain (see section 4.7.1). The
high partition coefficient is simply required to ensure that the drug can cross the
blood–brain barrier and access GABA-A receptors within the brain.
1.2.3.2 Hansch Effects and the Calculation of Partition Coefficients
As is apparent, partition coefficients (quantified by the logP value) are important con-
siderations in drug design. To be successful during the pharmacokinetic phase of drug
action, the drug molecule should demonstrate the right combination of lipid solubility
and water solubility. This property is best represented by the logP value. If the logP
value is too low, the compound is too water soluble and thus will be unable to penetrate
lipid barriers and will be excreted too rapidly; if the logP value is too high, the com-
pound is too lipid soluble and will be undesirably sequestered in fat layers. Being able to
predict these solubility properties is important to the process of drug design. Accordingly,
being able to determine, calculate, or predict logP values is highly desirable to the drug
designer.
The central importance of logP values in drug design and in determining the phar-
macokinetic properties of a drug was extensively studied by Hansch in the 1960s.
Hansch pioneered the importance of logP values in structure–activity relationship stud-
ies (see section 3.3.2.1). Hansch experimentally determined the logP values of many
drugs and showed the importance of these values in determining the ability of a drug to
penetrate into the brain. Over the past 35 years, many methods for theoretically calcu-
lating logP values have been devised. Hydrophobic fragmental constants (symbolized
byf) were introduced by Rekker (1977) to facilitate the theoretical determination of
DRUG MOLECULES: STRUCTURE AND PROPERTIES 29