Blockade of postjunctional vascular alpha ₁- and alpha ₂-adrenoceptors in pithed rat by the enantiomers of WB-4101

Summary

The enantiomers of WB-4101 were evaluated for their ability to antagonize the α₁-adrenoreceptor mediated pressor effect of cirazoline and the α₂-adrenoreceptor mediated pressor effect of UK-14,304 in pithed rats. The (S)-stereoisomer of WB-4101 was more potent than the enantiomeric (R)-isomer in antagonizing both cirazoline and UK-14,304. The difference in potency between the enantiomers in blocking cirazoline was 37-fold in contrast to an enantiomeric difference of less than 3-fold for antagonizing UK-14,304. Based on DR₂ values (i.e., dose of WB-4101 isomer in mg/kg required to produce a 2-fold rightward shift in the doseresponse curves of cirazoline and UK-14,304) obtained in vivo from Schild regressions, α₁/α₂ selectivity ratios were calculated. While the (S)-enantiomer displays a 187-fold selectivity for α₁-adrenoreceptors, the (R)-enantiomer is only approximately 13-fold selective for α₁-adrenoreceptors. These results indicate that the α₁- and α₂-adrenoreceptor blocking activity of WB-4101 resides predominantly in the (S)-enantiomer and that both enantiomers of WB-4101 are selective α₁-adrenoreceptor antagonists in vivo. However the degree of α₁-adrenoreceptor selectivity differs for each enantiomer, and the enantiometric activity ratios differ for each α-adrenoceptor subtype.