Receptor occupancy and brain free fraction.

This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.

SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'methyl-4'-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): a novel, potent and selective 5-HT1B receptor antagonist.

SB-616234-A possesses high affinity for human 5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pKi 8.3+/-0.2), and is over 100-fold selective for a range of molecular targets except h5-HT1) receptors (pKi 6.6+/-0.1). Similarly, affinity (pKi) for rat and guinea pig striatal 5-HT1B receptors is 9.2+/-0.1. In [35S]-GTPgammaS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA2 value of 8.6+/-0.2 whilst providing no evidence of agonist activity in this system. In [35S]-GTPgammaS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pKB of 8.4+/-0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 microM) potentiated electrically stimulated [3H]-5-HT release from guinea pig and rat cortical slices (S2/S1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg(-1) p.o.) caused a dose-dependent inhibition of ex vivo [3H]-GR125743 binding to rat striatal 5-HT1B receptors with an ED50 of 2.83+/-0.39 mg kg(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT(1B) autoreceptor antagonist that occupies central 5-HT1B receptors in vivo following oral administration.