NOVEL AND SELECTIVE PARTIAL AGONISTS OF 5-HT3 RECEPTORS .2. SYNTHESISAND BIOLOGICAL EVALUATION OF PIPERAZINOPYRIDOPYRROLOPYRAZINES, PIPERAZINOPYRROLOQUINOXALINES, AND PIPERAZINOPYRIDOPYRROLOQUINOXALINES

In continuation of our previous work on piperazinopyrrolothienopyrazin e derivatives, three series of piperazinopyridopyrrolopyrazines, piper azinopyrroloquinoxalines, and piperazinopyridopyrrolaquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifi cations performed within these new series led to structure-activity re lationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 recep tors with a selectivity higher than 10(6). Four of the high-affinity 5 -HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrr olopyrazine and the pyrroloquinoxaline series and were characterized i n vitro and in vivo as agonists or partial agonists. Compound 8a was a lso evaluated in the light/dark test where it showed potential anxioly tic-like activity at very low doses per os.