| Popis: |
2-Adrenoceptors, subdivided into ?2A, ?2B, and ?2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain ?2C-adrenoceptor blockade has also been suggested to be beneficial for antipsychotic action. However, comparing ?2-adrenoceptor subtype affinity is difficult due to significant species and methodology differences in published studies. Here, 3H-rauwolscine whole cell binding was used to determine the affinity and selectivity of 99 ?-antagonists (including antidepressants and antipsychotics) in CHO cells expressing human ?2A, ?2B, or ?2C-adrenoceptors, using an identical method to ? and ?1-adrenoceptor measurements, thus allowing direct human receptor comparisons. Yohimbine, RX821002, RS79948, and atipamezole are high affinity non-selective ?2-antagonists. BRL44408 was the most ?2A-selective antagonist, although its ?1A-affinity (81nM) is only 9-fold greater than its ?2C-affinity. MK-912 is the highest-affinity, most ?2C-selective antagonist (0.15nM ?2C-affinity) although its ?2C-selectivity is only 13-fold greater than at ?2A. There are no truely ?2B-selective antagonists. A few ?-ligands with significant ?-affinity were detected, for example, naftopidil where its clinical ?1A-affinity is only 3-fold greater than off-target ?2-affinity. Antidepressants (except mirtazapine) and first-generation antipsychotics have higher ?1A than ?2-adrenoceptor affinity but poor ?-affinity. Second-generation antipsychotics varied widely in their ?2-adrenoceptor affinity. Risperidone (9nM) and paliperidone (14nM) have the highest ?2C-adrenoceptor affinity however this is only 5-fold selective over ?2A, and both have a higher affinity for ?1A (2nM and 4nM, respectively). So, despite a century of yohimbine use, and decades of ?2-subtype studies, there remains plenty of scope to develop ?2-subtype selective antagonists. |
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