<br>α-肾上腺素受体拮抗剂、抗抑郁药和抗精神病药对人类 α1A、α1B 和 α1D-肾上腺素受体的亲和力和选择性。,Pharmacology Research & Perspectives

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α-肾上腺素受体拮抗剂、抗抑郁药和抗精神病药对人类 α1A、α1B 和 α1D-肾上腺素受体的亲和力和选择性。
Pharmacology Research & Perspectives ( IF 2.9 ) Pub Date : 2020-07-01 , DOI: 10.1002/prp2.602
Richard G W Proudman ₁ , Andre S Pupo ₂ , Jillian G Baker ₁

Affiliation

α1-肾上腺素受体拮抗剂广泛用于治疗高血压（例如多沙唑嗪）和良性前列腺肥大（BPH，例如坦索罗辛）。据报道，一些抗抑郁药和抗精神病药具有 α1 亲和力。本研究检查了 101 种临床药物和实验室化合物，以全面了解 α1-肾上腺素受体亚型亲和力和选择性。 [3H]哌唑嗪全细胞结合在稳定表达全长人 α1A、α1B 或 α1D 肾上腺素受体的 CHO 细胞中进行。正如预期的那样，多沙唑嗪是一种高亲和力非选择性 α1 拮抗剂，尽管其他化合物（例如环唑嗪、3-MPPI 和 ARC239）具有更高的亲和力。证实了几种高度 α1A 选择性拮抗剂（SNAP5089 的 α1A 选择性超过 1700 倍）。尽管所有化合物都表现出 α1 亲和力，但只有 BMY7378 具有 α1D 选择性，并且没有鉴定出 α1B 选择性化合物。苯氧苯扎明（用于嗜铬细胞瘤）和二苯胺在所有三种受体上均具有双组分结合抑制曲线。与硫代硫酸钠一起孵育消除了高亲和力成分，表明该部分是受体介导的。用于治疗高血压和 BPH 的药物具有非常相似的 α1A/α1B/α1D 肾上腺素受体药理学特征。选择性血清素再摄取抑制剂（抗抑郁药）与 α1 肾上腺素受体的亲和力较差。几种三环类抗抑郁药（例如阿米替林）和抗精神病药（例如氯丙嗪和利培酮）具有较高的 α1 肾上腺素受体亲和力，类似于或高于治疗高血压和 BPH 的 α 阻滞剂，而其他药物的 α1 亲和力较差（例如普罗替林、舒必利、氨磺必利和奥氮平）。对于已经服用三环类抗抑郁药和某些抗精神病药的人来说，添加 α 受体阻滞剂来治疗高血压或 BPH 可能没有什么好处。对不同抗精神病药的α受体阻滞潜力的认识可能会影响谵妄患者的药物选择，因为额外的低血压（例如脓毒症）可能是有害的。

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The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors.

α1‐adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1‐adrenoceptor subtype affinity and selectivity. [3H]prazosin whole‐cell binding was conducted in CHO cells stably expressing either the full‐length human α1A, α1B, or α1D‐adrenoceptor. As expected, doxazosin was a high‐affinity nonselective α1‐antagonist although other compounds (eg, cyclazosin, 3‐MPPI, and ARC239) had higher affinities. Several highly α1A‐selective antagonists were confirmed (SNAP5089 had over 1700‐fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B‐selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two‐component‐binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high‐affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D‐adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1‐adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1‐adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α‐blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.

更新日期：2020-07-24

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