The affinity and selectivity of alpha-adrenoceptor antagonists, antidepressants, and antipsychotics for the human alpha 1A, alpha 1B, and alpha 1D-adrenoceptors

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alpha 1-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 alpha 1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of alpha 1-adrenoceptor subtype affinity and selectivity. [3H]prazosin whole-cell binding was conducted in CHO cells stably expressing either the full-length human alpha 1A, alpha 1B, or alpha 1D-adrenoceptor. As expected, doxazosin was a high-affinity nonselective alpha 1-antagonist although other compounds (eg, cyclazosin, 3-MPPI, and ARC239) had higher affinities. Several highly alpha 1A-selective antagonists were confirmed (SNAP5089 had over 1700-fold alpha 1A selectivity). Despite all compounds demonstrating alpha 1 affinity, only BMY7378 had alpha 1D selectivity and no alpha 1B-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 alpha 1A/alpha 1B/alpha 1D-adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor alpha 1-adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high alpha 1-adrenoceptor affinities, similar to, or higher than, alpha blockers prescribed for hypertension and BPH, whereas others had poor alpha 1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of alpha blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the alpha-blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.




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Pharmacology Research & Perspectives. Chichester: John Wiley & Sons Ltd, v. 8, n. 4, 16 p., 2020.

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