Receptor occupancy from Cp free

iii 111

Thioridazine Clozapine Haloperidol Remoxipride Sulpiride 4.0 3.0 2.0 1.4 -0.6

Fig. 2.12 Receptor occupancy based on PET scanning and in vitro potency combined with free plasma drug concentration. Log D74 values shown below compound names.

2.11 Slow Offset Compounds 29

As for the more comprehensive set of non-CNS site antagonists, referred to above, efficacy is observed at around 75 % receptor occupancy. Noticeably the lipophilic antagonists, thioridazine, clozapine, haloperidol and remoxipride, are in direct equilibrium with the free drug concentration in plasma. In contrast sulpiride requires a free plasma concentration over 50-fold greater than that required if there was a simple direct equilibrium between the plasma concentration and the extracellular fluid of the brain. This difference in equilibrium between sulpiride and the lipophilic compounds is due to the poor penetration of this hydrophilic molecule across the blood-brain barrier. As explained above, the reasons for this are the low number of aqueous channels or pores in the capillary walls of the blood vessels of the brain, thereby restricting entry of hydrophilic compounds to the extracellular fluid of the CNS. Similar observations can be made for intracellular targets, whether enzymes or receptors. Here the need to penetrate the lipid core is reflected in the physicochem-istry of the endogenous agonists. For instance, steroid receptors are intracellular and steroids have log D74 values such as 3.3, 1.7 and 2.3 for testosterone, cortisol and cor-ticosterone respectively. These values contrast with the values for the endogenous agonists of G-protein-coupled receptors.

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