Journal of Pharmacology and Experimental Therapeutics · 1988 · 313 citations · 0 references
MedicinePharmacologyMolecular PharmacologyNeuropharmacologyPharmacodynamicsLigand BindingReceptor BindingReceptor PharmacologyAdrenergic AntagonistsAdrenergic Receptor AgonistsAdrenergic Receptor AntagonistsAlpha-adrenergic AgonistsAntagonist PotencyDrug Receptor PharmacologyPharmacological ClassificationReceptors
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.