[A new approach to innovating selective anxiolytics: pharmacological profile of a novel 5-HT1A agonist (tandospirone)]

Abstract

Tandospirone (sedil) is a newly developed anxiolytic drug that has a much higher selective affinity for 5-HT1A than dopamine D2 receptors without the binding affinities with noradrenergic, dopaminergic, cholinergic and GABAergic receptors. This agent binds with 5-HT1A receptors located in both 5-HT neurons in the raphe nucleus and other postsynaptic neurons to induce hyperpolarization of the neurons by opening the K+ channels to eventually inhibit the target neuronal activities. With repeated administrations of tandospirone, a decrease in 5-HT2A receptor population was observed. Behavioral studies in experimental animals have demonstrated that tandospirone inhibits conflict in Vogel methods, aggressive behavior and muricide in manners similar to those of diazepam. In addition, tandospirone showed antistress effects in experimental models and antidepressive effects in forced swimming tests. Unlike diazepam, tandospirone does not produce sedative, sleep-inducing, anticonvulsant, nor muscle relaxant effects at doses effective for conflict tests. Drug dependance, one of the serious problems with bezodiazepine, is not observed with repeated treatment of tandospirone in rats and monkeys. Furthermore, tandospirone has been reported to show a significantly more superior or equipotent effect to diazepam in controlling autonomic disturbances, psychiatric cardiovascular and vegetative syndromes as well as neurosis in double blind clinical studies. These effects are probably due to the selective action of tandospirone on 5-HT1A receptors in the limbic system to eventuate anxiolytic and antidepressant effects. A decrease in 5-HT2A receptor population with repeated treatment of tandospirone may have contributed to the antidepressive effect. Furthermore, 5-HT1A receptors relatively, selectively distributed in the limbic system are not involved in sedation, sleep or muscle relaxation. Such unwanted effects of benzodiazepines are thus not observed with tandospirone treatment.