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Abstract：
Highly selective drugs offer a way to minimize side-effects. For agonist ligands, this could be through highly selective affinity or highly selective efficacy, but this requires careful measurements of intrinsic efficacy. The α1-adrenoceptors are important clinical targets, and α1-agonists are used to manage hypotension, sedation, attention deficit hypersensitivity disorder (ADHD), and nasal decongestion. With 100 years of drug development, there are many structurally different compounds with which to study agonist selectivity. This study examined 62 α-agonists at the three human α1-adrenoceptor (α1A, α1B, and α1D) stably expressed in CHO cells. Affinity was measured using whole-cell 3 H-prazosin binding, while functional responses were measured for calcium mobilization, ERK1/2-phosphorylation, and cAMP accumulation. Efficacy ratios were used to rank compounds in order of intrinsic efficacy. Adrenaline, noradrenaline, and phenylephrine were highly efficacious α1-agonists at all three receptor subtypes. A61603 was the most selective agonist and its very high α1A-selectivity was due to selective α1A-affinity (>660-fold). There was no evidence of Gq-calcium versus ERK-phosphorylation biased signaling at the α1A, α1B, or α1D-adrenoceptors. There was little evidence for α1A calcium versus cAMP biased signaling, although there were suggestions of calcium versus cAMP bias the α1B-adrenoceptor. Comparisons of the rank order of ligand intrinsic efficacy suggest little evidence for selective intrinsic efficacy between the compounds, with perhaps the exception of dobutamine which may have some α1D-selective efficacy. There seems plenty of scope to develop affinity selective and intrinsic efficacy selective drugs for the α1-adrenoceptors in future.
摘要：
高选择性药物提供了一种最小化副作用的方法。对于激动剂配体，这可以通过高选择性亲和力或高选择性功效，但这需要仔细测量内在功效。α1-肾上腺素受体是重要的临床靶点,α1-激动剂用于控制低血压，镇静,注意缺陷超敏反应障碍（ADHD），和鼻充血。随着100年的药物开发，有许多结构不同的化合物，研究激动剂的选择性。这项研究检查了三种人α1-肾上腺素受体（α1A，α1B,和α1D）在CHO细胞中稳定表达。使用全细胞3H-哌唑嗪结合测量亲和力，虽然测量了钙动员的功能反应，ERK1/2-磷酸化，和cAMP积累。使用功效比率按照内在功效的顺序对化合物进行排序。肾上腺素,去甲肾上腺素,和去氧肾上腺素对所有三种受体亚型都是高效的α1-激动剂。A61603是最具选择性的激动剂,并且其非常高的α1A选择性是由于选择性α1A亲和力(>660倍)。在α1A上没有Gq-钙与ERK-磷酸化偏向性信号的证据，α1B,或α1D-肾上腺素受体。几乎没有证据表明α1A钙与cAMP偏向信号，尽管有建议钙与cAMP偏向α1B-肾上腺素受体。配体内在功效的等级顺序的比较表明，几乎没有证据表明化合物之间的选择性内在功效，多巴酚丁胺可能有一些α1D选择性功效。未来似乎有很多范围来开发用于α1-肾上腺素受体的亲和选择性和内在功效选择性药物。
