Penetration barrier

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. 

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. 

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. 

Fig. 2.7. Coulomb barrier penetration by a charged particle, a is the range of the nuclear force and b the classical turning point.

The matrix elements in angle brackets contain nuclear factors and (in the case of charged particles) the Coulomb barrier penetration probabilities or Gamow factors, originally calculated in the theory of a-decay, which can be roughly estimated as follows (Fig. 2.7). 

Since a / (typically by a factor of order 100), the factor in brackets is nearly 7r/2 and is quite insensitive to the value of a. Numerically, the barrier penetration probability for 5-waves is thus... 

A more exact expression for the barrier penetration factor, derived for example by Clayton (1968), is... 

R. Atkinson and F. Houtermans apply Gamow s theory of potential barrier penetration by quantum tunnelling to suggest how stars can release nuclear energy by synthesis of hydrogen into helium by an (unspecified) cyclic process. 

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. 

For typical outer-sphere exchanges at ordinary temperatures, it seems probable that the original assumption of Hush and of Marcus that barrier penetration is a comparatively minor effect is correct. Moreover> it is, in a particular case, quite simple to calculate. The more general questions to which we do not yet have an answer are how adequate is the Golden Rule approach in discussing tunnelling, and, in particular, what would be expected for systems strictly remaining on one surface (electronically adiabatic) A number of fundamental issues involved here have been discussed in a recent series of papers (42-45). 

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