L-765314

L-765314 is a potent and selective α1b adrenergic receptor antagonist with K_is of 5.4 nM and 2.0 nM for rat and human α1b adrenergic receptor, respectively. IC50 & Target:Ki: 5.4 nM (rat α1b receptor ), 2.0 nM (human α1b receptor), 50 (rat α1d receptor), 34 nM (human α1d receptor), 500 nM (rat α1a receptor ), 420 nM (human α1a receptor)^[1]. In Vitro:L-765314 exhibits two displacement sites. The high-affinity site accounts for approximately 25% of binding (IC₅₀) 1.90 nM and represents binding to the R1b sites. The low-affinity site accounts for the residual 75% of binding (IC₅₀) 790 nM and represents binding to the R1a sites^[1]. In Vivo:The results of plasma assayed by liquid chromatograph/mass spectrometer (LCMS) show that the mean C_max of L-765314 (A322312) is 1.05 μM and the t_1/2 is 0.5 h. L-765314 shows weak potency for inhibiting the pressor response to either phenylephrine or A-61603 (AD₂₅>3 mg/kg for each). On the basis of the inhibition of pressor responses to the R1a subtype selective agonist A-61603, L-765314 appears to be selective versus the R1a receptor up to a dose of 0.3 mg/kg. The results of hypotensive potency in rats show that both L-765314 and terazosin tend to decrease heart rate (about 25 bpm at 1 mg/kg iv)^[1].