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Alpha-2A and alpha-2B adrenergic receptor subtypes: antagonist binding in tissues and cell lines containing only one subtype.
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1988
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Alpha‑2 adrenergic receptors are divided into alpha‑2A and alpha‑2B subtypes, with oxymetazoline selective for alpha‑2A and prazosin selective for alpha‑2B. The study aimed to establish a cell line for each subtype to facilitate further research on alpha‑2 adrenergic receptor pharmacology. Thirty‑four adrenergic antagonists were evaluated by radioligand binding to [³H]yohimbine and [³H]rauwolscine in five tissues that express only one subtype (human platelet, HT29, cerebral cortex for alpha‑2A; neonatal rat lung, NG108‑15 for alpha‑2B). Drug affinities correlated strongly within the same subtype (r = 0.97–0.99) but poorly across subtypes (r = 0.77 to –0.87), and three new alpha‑2B selective antagonists (ARC‑239, chlorpromazine, 7‑hydroxychlorpromazine) were identified, confirming distinct pharmacological profiles for the two subtypes.
The affinities of 34 adrenergic antagonists for alpha-2 adrenergic receptors were determined from homogenate radioligand binding studies using [3H]yohimbine and [3H]rauwolscine. It has been suggested that alpha-2 adrenergic receptors can be subdivided into alpha-2A and alpha-2B subtypes. Oxymetazoline is selective for alpha-2A receptors, whereas prazosin is alpha-2B selective. Five different tissues were used, each of which has only one of the two subtypes: human platelet (alpha-2A), HT29 cell line (alpha-2A), human cerebral cortex (alpha-2A), neonatal rat lung (alpha-2B), and NG108-15 cell line (alpha-2B). The drug affinities were highly correlated when alpha-2A tissues were compared with alpha-2A tissues (r = 0.97 to 0.98) or when the two alpha-2B tissues were compared (r = 0.99). By contrast, comparison of an alpha-2A tissue with an alpha-2B tissue resulted in poor correlations (r = 0.77 to -0.87). Three new subtype selective drugs were identified among these drugs on the basis of at least a 10-fold greater affinity for one subtype. All three were selective for the alpha-2B subtype: ARC-239 (100-fold selective), chlorpromazine (18-fold selective), and 7-hydroxychlorpromazine (17-fold selective). These studies, by demonstrating distinct pharmacological profiles for the two alpha-2 adrenergic receptor subtypes in several different tissues, further support the existence and definition of these subtypes. The identification of a cell line for each subtype should be useful in the further study of alpha-2 adrenergic receptor subtypes.