Novel, Potent, and Selective Quinoxaline-Based 5-HT3 Receptor Ligands. 1. Further Structure-Activity Relationships and Pharmacological Characterization

We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT3 receptor ligands bearing an extra basic moiety oil the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold-Jarisch reflex test 3a-c were partial agonists while 3i was a full agonist. Preliminary pharmacokinetic studies indicated that 3a is it brain penetrating agent.