Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists: Synthesis, further structure-activity relationships, and biological studies

The synthesis, pharmacological evaluation, and structure-activity relations hips (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-rel ated derivatives are described. The new pyrroloquinoxaline-related ligands were tested in rat cortex, a tissue expressing high density of 5-HT3 recept ors, and on NG108-15 cells and exhibited IC50 values in the low nanomolar o r subnanomolar range, as measured by the inhibition of [H-3]zacopride bindi ng. The SAR studies detailed herein delineated a number of structural featu res required for improving affinity. Some of the ligands were employed as " molecular yardsticks" to probe the spatial dimensions of the lipophilic poc kets L1, L2, and L3 in the 5-HT3 receptor cleft, while the 7-OH pyrroloquin oxaline analogue was designed to investigate hydrogen bonding with a putati ve receptor site H1 possibly interacting with the serotonin hydroxy group. The most active pyrroloquinoxaline derivatives showed subnanomolar affinity for the 5-HT3 receptor. In functional studies ([C-14]guanidinium accumulat ion test in NG108-15 hybrid cells, in vitro) most of the tested compounds s howed clear-cut 5-HT3 agonist properties, while some others were found to b e partial agonists. Several heteroaromatic systems, bearing N-substituted p iperazine moieties, have been explored with respect to 5-HT3 affinity, and novel structural leads for the development of potent and selective central 5-HT3 receptor agonists have been identified. Preliminary pharmacokinetic s tudies indicate that these compounds easily cross the blood-brain barrier ( BBB) after systemic administration with a brain/plasma ratio between 2 and 20, unless, they bear a highly hydrophilic group on the piperazine ring. No ne of the tested compounds showed in vivo anxiolytic-like activity, but pot ential analgesic-like properties have been possibly disclosed for this new class of 5-HT3 receptor agonists.