Blood-Brain-Barrier Penetration

Computational models for blood-brain-barrier penetration have been well reviewed in detail by Clark [36]. Penetration of the blood-brain-barrier (BBB) via passive diffusion is dependent upon the hydrophilicity and lipophilicity of a molecule. However, the BBB is a thicker, more lipophilic membrane than the intestinal membrane. Kelder et al. [37] showed that very few of 776 orally administered CNS drugs had PSA 90, while a substantial fraction of 1590 orally administered non-CNS had PSA 90. These results demonstrate the poor BBB penetration by hydrophilic molecules. 

The calculated cross-sectional area of a molecule (Aocaic) based on the internal amphiphilic gradient of a molecule has been used as the basis for a novel BBB model [40]. For each molecule, a conformational ensemble was generated and the smallest ADca c was chosen. A simple bi-plot of log D7A vs. ADcaic was sufficient to correctly predict the BBB penetration of 85.2% of 122 drugs. 

In a study of p-glycoprotein substrates vs. non-substrates, Varma et al. [48] concluded that substrate molecules with high passive permeability overwhelmed the transporter while substrate molecules with moderate passive permeability were more affected by p-glycoprotein. Approximately half of 63 p-glycoprotein substrates studied had MW 400 and PSA 75 indicating that larger, more polar molecules are more likely to be p-glycoprotein substrates. 

Cabrera et al. [50] modeled a set of 163 drugs using TOPS-MODE descriptors with a linear discriminant model to predict p-glycoprotein efflux. Model accuracy was 81% for the training set and 77.5% for a validation set of 40 molecules. A combinatorial QSAR approach was used by de Lima et al. [51] to test multiple model types (kNN, decision tree, binary QSAR, SVM) with multiple descriptor sets from various software packages (MolconnZ, Atom Pair, VoSurf, MOE) for the prediction of p-glycoprotein substrates for a dataset of 192 molecules. Best overall performance on a test set of 51 molecules was achieved with an SVM and AP or VolSurf descriptors (81% accuracy each). 

The half-life (f%) of a drug is related to the volume of distribution (Vd) and clearance (CL) by the equation f% = 0.693 x Vd/CL. The volume of distribution at a steady-state (Vss) is related to the volume of plasma, tissue, and fraction of the drug unbound in plasma and tissue. 

The BBB is a complex cellular system which protects the central nervous system (CNS) by separating the brain from the systemic blood circulation. Drugs that act 

Kelder et al. [25] collected a set of 776 orally administered CNS drugs that are known to be passively transported into the brain and have entered at least phase 

In a recent study involving 150 chemically diverse compounds [26] the following global BBB penetration model was obtained  

The authors noted, however, that the separation of compounds into chemically similar classes considerably improves the construction of predictive BBB penetration models. 

Numerous other QSAR models relating BBB penetration to calculated molecular descriptors have also appeared in literature see for example [27-29]. In each case, PSA was identified as one of the most important parameters determining blood-brain barrier penetration. 

---

Li H, Yap CW, Ung CY, Xue Y, Cao ZW and Chen YZ Effect of selection of molecular descriptors on the prediction of blood-brain barrier penetrating and nonpenetrating agents by statistical learning methods. J Chem Inf Model 2005 45 1376-1384. 

Goodwin IT and Clark DE., In silico predictions of blood-brain barrier penetration considerations to keep in mind . J Pharmacol Exp Ther 2005. 

Clark, D. E. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration. J. Pharm. Sci. 1999, 88, 815-821. 

Prediction of blood-brain barrier penetration. J. Pharm. Sci. 1999, 88, 815-821. 

The generic term of drug-likeness implies a number of other properties [24] such as aqueous solubility, metabolism, blood-brain barrier penetration and oral absorption which are covered by other chapters in this book. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Pharmacodynamics Duration 1-4 weeks Absorption IM slow Time to peak serum levels 12-24 hours Duration 15-24 hours Absorption IM slow Distribution Poor blood-brain barrier penetration, enters breast milk Metabolism =30% hepatic inactivation Protein binding 65% Time to peak serum levels 1-4 hours Excretion Urine (60-90% as unchanged drug) Clearance Renal... 

Clark, D. E., Prediction of intestinal absorption and blood-brain barrier penetration by computational methods, Comb. Chem. High Throughput Screen., 2001, 4, 477—496. 

Fu XC, Chen CX, Liang WQ, Yu QS (2001) Predicting blood-brain barrier penetration of drugs by polar molecular surface area and molecular volume. Acta Pharmacol Sin 22 663-668. 

Liu R, Sun H, So SS (2001) Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration. J Chem Inf Comput Sci 41 1623-1632. 

Ma XL, Chen C, Yang J (2005) Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacol Sin 26 500-512. 

There are several efflux pumps which may affect absorption, blood-brain-barrier penetration, and reabsorption from kidney microtubules. The most commonly tested efflux pump in early drug discovery is the P-glycoprotein. Assays to identify P-glycoprotein substrates or inhibitors can be run using a variety of cell lines. 

Obrezanova, O., Gola, J.M.R., Champness, E.J., Segall, M.D. Automatic QSAR modeling of ADME properties blood-brain barrier penetration and aqueous solubility. J. Comput. Aided Mol. Des. 2008, 22, 431—40. 

Naive Bayesian classifier Intestinal absorption (passive), blood-brain barrier penetration, serum protein binding Classifier No [17]... 

Feng, M.R. (2002) Assessment of blood-brain barrier penetration In silko, in vitro and in vivo. Current Drug Metabolism, 3, 647-657. 

While effects of P-glycoprotein polymorphisms have been reported for intestinal uptake, no such studies exist for effects on blood-brain barrier penetration. If certain polymorphisms were to alter intracerebral concentrations of specific antidepressants, prior knowledge of the patients relevant P-glycoprotein genotypes could prevent the administration of a drug that might never reach therapeutic intracerebral levels despite a normal plasma concentration. 

Derivatization of kynurenic acid leads to far more potent and selective antagonists such as 7-chloro-kynurenic acid or 5,7-dichlorokynurenic acid (Kemp et al., 1988 Baron et al., 1990) which have been shown to inhibit glycine-induced tailflick facilitation (i.e attenuation of glycine-induced hyperalgesia) or the late phase of formalin-induced nociception when given intrathecally (Kolhekar et al., 1994, Chapman et al., 1995). Nevertheless kynurenic acid derivatives are still hampered by a poor blood - brain barrier penetration and hence a low CNS availability. 

---