Characterization of subtypes of alpha-2 adrenoceptors in the human brain

Radioligand binding studies have demonstrated that oxymetazoline has a high affinity for alpha-2A receptors, but lower affinities for alpha-2B and alpha-2C receptors. In contrast, prazosin has high affinity for alpha-2B and alpha-2C receptors, but relatively lower affinity for alpha-2A receptors. We exploited the respective selectivity of oxymetazoline and prazosin for alpha-2A and alpha-2B/2C adrenoceptors, respectively, to describe pharmacologically and to locate neuroanatomically alpha-2 adrenoceptor subtypes in the human brain. Competition curves for the inhibition of [3H]yohimbine binding by oxymetazoline and prazosin in homogenates of human caudate nucleus were fit best by a model assuming binding to two sites (P < .005). A concentration (CONCopt) of oxymetazoline and prazosin was calculated from these curves that would optimally antagonize binding of [3H]yohimbine to high-affinity sites, minimally inhibiting low-affinity binding. In the presence of CONCopt of prazosin, competition studies of remaining [3H]yohimbine binding in cerebral cortex revealed a rank order potency and potency ratios of compounds which were characteristic of alpha-2A receptors. In the presence of CONCopt of oxymetazoline, competition studies of remaining [3H]yohimbine binding in caudate revealed a rank order potency and potency ratios of compounds which were characteristic of alpha-2C receptors. The existence of a small population of alpha-2B adrenoceptors in the caudate could not be ruled out because slopes of competition curves of compounds which distinguish alpha-2B and alpha-2C adrenoceptors were shallow at oxymetazoline-insensitive sites. The percentages of [3H]yohimbine binding that were inhibited by the CONCopt of oxymetazoline and prazosin were determined in numerous brain regions. Oxymetazoline-sensitive binding of [3H]yohimbine predominated in most regions except for the caudate nucleus, where prazosin-sensitive binding was greatest.