Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties

Article abstract of DOI:10.1021/jm0493461

Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine₃ (5-HT₃) receptor. Most of the new compounds show subnanomolar 5-HT₃ receptor affinity. Ester 6bc showing a picomolar K_i value is one of the most potent 5-HT ₃ receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 60 was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT₃ receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT₃ receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT₃ receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.