NOVEL AND HIGHLY POTENT 5-HT3 RECEPTOR AGONISTS BASED ON A PYRROLOQUINOXALINE STRUCTURE

The synthesis and the biological evaluation of a series of novel pyrro loquinoxaline derivatives are described. In binding studies several co mpounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar af finity for 5-HT3 receptor and were able to functionally discriminate t he central and peripheral 5-HT3 receptors, being agonists and antagoni sts, respectively. In functional studies ([C-14]-guanidinium accumulat ion test in NG 108-15 cells, in vitro) most of the synthesized compoun ds showed clear-cut 5-HT3 agonist properties. In in vivo studies on th e von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, wh ile clear agonist properties were obtained with 12a on cortical acetyl choline release in freely moving rats. Pharmacokinetic studies with 11 e and 12c indicate that the compounds easily cross the blood-brain bar rier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.