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Abstract
Starting from the potent and selective but poorly brain penetrant 5-HT 6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT 6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT 6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
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