(i) LIPOPHILICITY (e.g., LogD and cLogP). Historically, lipophilicity was the ﬁrst of the structural properties to be recognized as important for CNS penetration. As early as 1897, Overton observed correlations between oil-water partition coefficients and narcotic potencies of a series of compounds in tadpoles . By the 1960s, Hansch introduced the octanol/water system, which became the standard for measuring partition coefficients, and he demonstrated that blood-brain barrier permeation is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1. In line with Hansch’s findings, the mean value for cLogP for 74 marketed CNS drugs has been reported by Leeson to be 2.5. A number of different guidelines for predicting BBB permeation based on structural properties have been proposed, which suggests preferred ranges for LogP of between 1 and 5 (Table 1). In addition to permeability, lipophilicity plays an important role in other pharmacokinetic properties that may affect the efficacy of a CNS drug. For example, high lipophilicity will reduce aqueous solubility, and it can contribute to excessive volumes of distribution, and increased metabolic liability.
(ii) MOLECULAR WEIGHT (MW). CNS drugs tend to have lower MW compared with other therapeutics; for marketed CNS drugs, the mean value of MW is 310, whereas the average MW of all marketed oral drugs is 377. Rules for predicting BBB tend to place the MW cutoff for BBB penetration in the 400-500 Da range (Table 1).
(iii) POLAR SURFACE AREA (PSA). The importance of PSA as a predictor for BBB penetration was first introduced by van de Waterbeemd and Kansy in the early 1990s. The PSA for marketed CNS drugs (estimated at 50-60 Å2) is signiﬁcantly less than that for all marketed oral drugs (estimated at 100–110 Å2). The suggested cutoffs for BBB penetration are, generally, to keep PSA values below 70-90 Å2 (Table 1). As the PSA of a molecule rises above this cut off, the potential for poor passive permeability increases. However, a compound with a quaternary nitrogen atom may have a low PSA value, but it is highly unlikely to permeate a membrane via passive diffusion. Conversely, some compounds with very high PSA values still may cross membranes, if they are substrates for active transport systems or if the polarity is masked (e.g., internal H-bonding).
(iv) HYDROGEN BONDING. Closely related to PSA and the potential to cross the BBB is the hydrogen bonding capability of a molecule. On average, marketed CNS drugs contain 2.1 hydrogen bond acceptors and 1.5 hydrogen bond donors, considerably less than the 3.7 hydrogen bond acceptors and 1.8 hydrogen bond donors for all oral drugs .
(v) CHARGE. The majority of marketed CNS drugs contain a basic amine group. At physiological pH (e.g., pH 7.4), basic amines exist in equilibrium between the charged and neutral forms, with the greater fraction of neutrals favoring partition into membrane lipids and brain permeation. By contrast, a strong acid (pKa <4) or a strong base (pKa >10) will be fully ionized at physiological pH, and these compounds rarely penetrate the BBB unless by active transport . Guidelines limiting the pKa of a compound to between 4 and 10 for a CNS compound have been suggested .