Blood brain-penetration

G. Fillion, B. Dupraz, N. Prudhomme, T. Huynh-Dinh, Blood-Brain Penetration of 5-Hydroxytryptamine Derivatives , Bioorg. Med. Chem. Lett. 1994, 4, 1485-1490. 

The complex contribution of hydrophobicity (log P) to various biological end-points is illustrated by examples drawn from the central nervous system (blood-brain penetration), absorption (intestinal absorption), metabolism... 

Blood-brain penetration PermabiUty Efflux (pGp) Active transports LipophyUcity... 

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Cancer chemothCTapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. Diaziquone (at one time known as AZQ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [.55J. 

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. 

In view of the preponderance of muscarinic receptors in the CNS and the conceived need to augment the muscarinic actions of ACh in the treatment of Alzheimer s disease, much attention has been given recently to the synthesis of agonists that penetrate the blood-brain barrier, especially those that act specifically on M] receptors. 

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. 

Reichel, A., Begley, D. J. Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier. Pharm. Res. 1998, 35,1270-1274. 

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.

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

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