SB-224289 hydrochloride (SB-224289A) is a selective antagonist of 5-HT1B receptor, with anxiolytic effect.

SB-224289 demonstrates specific toxin-blocking properties without directly inhibiting the PS synthase enzyme or Cho1p in vitro. It consistently shows efficacy in producing Pap-A resistance at concentrations ranging from 100 μM to 25 μM and uniquely blocks the activity of papuamides, without affecting other membrane disruptors. Although SB-224289 does not protect wild-type cells from KF, it offers protection against TPap-A. It possesses a high affinity, with a pKi of 8, for human cloned 5-HT1B receptors, showing greater than 80-fold selectivity compared to the 5-HT1D receptor and other receptor types. As a potent antagonist (with a pEC50 of 7.9±0.1), SB-224289 induces a rightward shift in the 5-HT concentration response curve (with a pA2 of 8.4±0.2) and significantly enhances [3H]-5HT release in electrically stimulated guinea-pig brain cortex slices at 100 nM and 1 μM concentrations.

SB 224289 is a potent antagonist with an ED50 of 3.6 mg/kg, p.o in SK&F-99101-induced hypothermia in the guinea-pig. SB 224289 (4 mg/kg, p.o) reverses sumatriptan-induced inhibition of 5-HT release showing that it is also a potent terminal 5-HT autoreceptor antagonist in vivo. SB 224289 (2-16 mg/kg, p.o) does not increase 5-HT levels in the fuinea-pig frontal cortex. However, SB 224289 (4 mg/kg, p.o) causes a significantly increase in levels of 5-HT in the fuinea-pig dentate gyrus[3].