| In Vitro | In vitro activity: SB-271046 also potently displaces [125I]-SB-258585 from rat and pig striatal and human caudate putamen membranes with pKis of 9.02, 8.55 and 8.81, respectively. SB-271046 competitively antagonizes 5-HT-induced stimulation of adenylyl cyclase activity with a pA2 of 8.71. SB-271046 is found to be a competitive antagonist with a pA2 of 8.7 in the functional adenylyl cyclase assay which is in good agreement with its binding affinity. SB-271046 demonstrates no significant inhibitory activity at the major human P450 enzymes.
Kinase Assay: SB271046 Hcl is a potent, selective and orally active 5-HT6 receptor antagonist with pKi of 8.9. IC50 Value: 8.9(pKi). SB 271046 hydrochloride is a sulfonamidal benzothiophene derivative that has been shown to act as a selective 5-HT6 antagonist with pKi values of 9.02-8.92, 6.55, 6.35, 6.27, 6.05, 5.95, 5.76, 5.73, 5.62, 5.55, 5.41, 5.39, 5.27 and < 4.99 for 5-HT6, 5-HT1D, 5-HT1A, D3, 5-HT1B, 5-HT1F, α1B, 5-HT2C, 5-HT2A, D2, 5-HT2B, 5-HT7, 5-HT4 and 5-HT1E respectively, and is > 200-fold selective over 55 other receptors, enzymes and ion channels. |
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| In Vivo | SB-271046 produces an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of 0.1 mg/kg p.o. and maximum effect at 4 hours post-dose. The level of anticonvulsant activity achieves correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 μM) and brain concentrations of 0.01 μM–0.04 μM at Cmax. SB-271046 is moderately brain penetrant (10%), subject to low blood clearance (7.7 mL/min/kg) with a good half-life in rats (4.8 hours), and has excellent oral bioavailability (>80%). SB-271046 produces 3-fold and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus of rats, respectively, which may be used for the treatment of cognitive and memory dysfunction. SB-271046 (20 mg/kg, orally gavage) 30 min prior to training Wistar rats, is found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, i.p.) in the 6 hours post-training period. SB-271046 progressively and significantly decreases platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls in aged rats. SB-271046 also improves task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3. SB-271046 (10 mg/kg, s.c.) produces a significant, tetrodotoxin-dependent, increase in extracellular levels of both glutamate and aspartate within the frontal cortex of rats, reaching maximum values of 375.4% and 215.3% of preinjection values, respectively. |
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