The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors
Abstract 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 com...
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.602 |
| _version_ | 1828978836140720128 |
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| author | Richard G. W. Proudman Andre S. Pupo Jillian G. Baker |
| author_facet | Richard G. W. Proudman Andre S. Pupo Jillian G. Baker |
| author_sort | Richard G. W. Proudman |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-14T15:26:40Z |
| format | Article |
| id | doaj.art-510f385e83cc4e3dba11141b3a79376c |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-14T15:26:40Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-510f385e83cc4e3dba11141b3a79376c2022-12-21T22:56:01ZengWileyPharmacology Research & Perspectives2052-17072020-08-0184n/an/a10.1002/prp2.602The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptorsRichard G. W. Proudman0Andre S. Pupo1Jillian G. Baker2Cell Signalling Research Group Division of Physiology, Pharmacology and Neuroscience School of Life Sciences C Floor Medical School Queen’s Medical CentreUniversity of Nottingham Nottingham UKDepartment of Pharmacology Institute of Biosciences São Paulo State University Botucatu‐São Paulo BrazilCell Signalling Research Group Division of Physiology, Pharmacology and Neuroscience School of Life Sciences C Floor Medical School Queen’s Medical CentreUniversity of Nottingham Nottingham UKAbstract 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.https://doi.org/10.1002/prp2.602affinityantidepressantantipsychoticbenign prostatic hypertrophyhypertensionα antagonist |
| spellingShingle | Richard G. W. Proudman Andre S. Pupo Jillian G. Baker The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors Pharmacology Research & Perspectives affinity antidepressant antipsychotic benign prostatic hypertrophy hypertension α antagonist |
| title | The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors |
| title_full | The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors |
| title_fullStr | The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors |
| title_full_unstemmed | The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors |
| title_short | The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors |
| title_sort | affinity and selectivity of α adrenoceptor antagonists antidepressants and antipsychotics for the human α1a α1b and α1d adrenoceptors |
| topic | affinity antidepressant antipsychotic benign prostatic hypertrophy hypertension α antagonist |
| url | https://doi.org/10.1002/prp2.602 |
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