The effects of AP521,a novel anxiolytic drug,in three anxiety models and on serotonergic neural transmission in rats

We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug,(r)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (ap521). ap521 showed equal or more potent anxiolytic-like effects compared with diazepam,a benzodiazepine receptor agonist,or tandospirone,a partial 5-hydroxytryptamine (5-ht)1a receptor agonist,in three rat anxiety models; the vogel-type conflict test,elevated plus maze test,and conditioned fear stress test. although ap521 did not bind to the benzodiazepine receptor,it did bind to 5-ht1a,5-ht1b,5-ht1d,5-ht5a and 5-ht7 receptors,and showed agonist activity for the human 5-ht1a receptor expressed in hek293 cells. tandospirone,which can stimulate the presynaptic 5-ht1a receptors in the raphe,tended to decrease extracellular 5-ht concentration in the medial prefrontal cortex (mpfc) in rats. in contrast,ap521 increased extracellular 5-ht concentration. in addition,ap521 enhanced the anti-freezing effect of citalopram,a selective serotonin reuptake inhibitor,in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-ht concentration in the mpfc. these results suggest that ap521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-ht1a receptor agonist and by enhancing serotonergic neural transmission in the mpfc by a novel mechanism of action. © 2014 japanese pharmacological society.