Four pharmacological subtypes of the alpha-2 adrenergic receptor have been identified; however, only three subtypes exist in any given species. Although the alpha-2A adrenergic receptor, as defined by the human platelet, and the alpha-2D receptor, as defined in the bovine pineal, have very different pharmacological characteristics, they are more similar to each other than either is to the alpha-2B or alpha-2C subtype. The human alpha-2-C10 clone (alpha-2A) and the rat RG20 clone have an 89% identity in their predicted amino acid sequence and are considered to be species orthologs. Although the expressed RG20 clone appears to have alpha-2D pharmacology, a careful comparison of its pharmacological characteristics with the bovine pineal has not been reported previously. Based on the pKi values of a panel of 13 alpha-2 adrenergic agents that have been used previously to compare the alpha-2A, alpha-2B and alpha-2C subtypes, the pharmacological characteristics of the bovine pineal alpha-2D receptor appear to be very similar to the rat RG20 clone (correlation coefficient, r, of 0.93). The porcine ortholog of the human alpha-2-C10 receptor has pharmacological characteristics identical to the human alpha-2A receptor (r = 0.99). Because of its higher affinity for the alpha-2D receptor, [3H]RX821002 is a better radioligand than [3H]rauwolscine for studying this receptor subtype.