Tasipimidine-the pharmacological profile of a novel orally active selective α_2A-adrenoceptor agonist

The pharmacological profile of tasipimidine, a novel orally active α₂-adrenoceptor agonist developed for situational anxiety and fear in dogs, was studied in various in vitro and in vivo models. In the cell assays, tasipimidine demonstrated binding affinity and full agonism on the human α_2A-adrenoceptors with a pEC50 of 7.57, while agonism on the α_2B-and α_2C-adrenoceptors and the rodent α_2D-adrenoceptor was weaker, resulting in pEC50 values of 6.00, 6.29 and 6.56, respectively. Tasipimidine had a low binding affinity on the human α₁-adrenoceptors. It had no functional effects in the LNCaP cells expressing endogenously the human α_1A-adrenoceptors but was a weak agonist in the Chem-1 cells coexpressing Gα15 protein and α_1A-adrenoceptors. In the recombinant CHO cells, although tasipimidine was a weak partial agonist in the inositol monophosphate accumulation assay, it was a full agonist in the intracellular [Ca²⁺] assay. No functional effects were observed on the human α_1B-adrenoceptor, whereas in the rat α_1A and α_1B-adrenoceptors, tasipimidine was a weak partial agonist. In the rat vas deferens preparations, tasipimidine was a full agonist on the α_2D-adrenoceptor but weak partial agonist on the α₁-adrenoceptor. The receptor profile of tasipimidine indicated few secondary targets, and no functional effects were observed. Sedative effects of tasipimidine were demonstrated in vivo by the reduced acoustic startle reflex in rats with subcutaneous doses and decreased spontaneous locomotor activity in mice with subcutaneous and higher oral doses. It may be concluded that tasipimidine is an orally active and selective α_2A-adrenoceptor agonist.