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)b iphenyl-4 - yl]methanone hydrochloride): A novel, potent and selective 5-HT sub(1B) receptor antagonist

SB-616234-A possesses high affinity for human 5-HT sub(1B) receptors stably expressed in Chinese hamster ovary (CHO) cells (pK sub(i) 8.3 +/- 0.2), and is over 100-fold selective for a range of molecular targets except h5-HT sub(1D) receptors (pK sub(i) 6.6 +/- 0.1). Similarly, affinity (pK sub(i)) for rat and guinea pig striatal 5-HT sub(1B) receptors is 9.2 +/- 0.1. In [ super(35)S]-GTP gamma S binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA sub(2) value of 8.6 +/- 0.2 whilst providing no evidence of agonist activity in this system. In [ super(35)S]-GTP gamma S binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pK sub(B) of 8.4 +/- 0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 mu M) potentiated electrically stimulated [ super(3)H]-5-HT release from guinea pig and rat cortical slices (S sub(2)/S sub(1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg super(-1) p.o.) caused a dose-dependent inhibition of ex vivo [ super(3)H]-GR125743 binding to rat striatal 5-HT sub(1B) receptors with an ED sub(50) of 2.83 +/- 0.39 mg kg super(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT sub(1B) autoreceptor antagonist that occupies central 5- HT sub(1B) receptors in vivo following oral administration.