Abstract
<b>Abstract ID 54729</b> <b>Poster Board 527</b> RS17053 is classed as an alpha1A-adrenergic receptor (alpha1A-AR) selective antagonist but has actions distinct from those of the commonly used alpha1A-AR antagonist RS100329. In radioligand binding studies, RS17053 shows affinities (-logM) of 8.74, 7.24 and 7.25 at alpha1A-, alpha1B- and alpha1D-ARs, respectively (mean of 3 published studies). We have examined its profile of action in functional studies at all subtypes of alpha1-AR. We have studied isometric contractions of rat aortic rings and rat vas deferens in organ bath studies of contractions to norepinephrine (NE). Isometric contractions evoked by NE in vas deferens involve alpha1D-adrenoceptors in the phasic component, and alpha1A-ARs in the tonic component to contractions. RS17053 (10<sup>-5</sup>M) shifted NE potency and virtually abolished tonic contractions to NE, with little or limited effects on phasic contractions. The alpha1D-AR antagonist BMY7378 (3x10<sup>-7</sup>M) significantly reduced the remaining phasic component of the contractions, and the alpha1A-AR antagonist RS100329 (10<sup>-7</sup>M) further blocked the residual tonic contraction. Hence, RS17053 shows high selectivity for alpha1A-ARs over alpha1D-ARs in rat vas deferens. Isometric contractions of rat aortic rings to NE involve alpha1D- and alpha1B-ARs. However, RS17053 (10<sup>-5</sup>M) produced a large shift in the potency of NE in rat aorta, with a pK<sub>B</sub> of 6.82. Large shifts of NE potency in rat aorta are consistent with actions at least partly involving block of alpha1B-ARs. In summary, results in rat vas deferens demonstrate low potency of RS17053 at alpha1D-ARs, but results from rat aorta can only be explained as demonstrating alpha1B-AR antagonism by RS17053. In conclusion, RS17053 is an alpha1A-AR antagonist with high potency at alpha1A-ARs in rat vas deferens, intermediate potency at alpha1B-ARs in rat aorta resulting in limited alpha1A-AR selectivity, but we have found surprisingly low potency at alpha1D- ARs in rat vas deferens. This differs from the ligand binding profile. This functional profile may make RS17053 a useful pharmacological tool.
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