| Abstract
| - Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, andevaluated 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 apicomolar Ki value is one of the most potent 5-HT3 receptor ligands so far synthesized. Thestructure−affinity relationship study suggests the existence of a certain degree of conformationalfreedom of the amino acid residues interacting with the substituents in positions 3 and 4 ofthe quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o wasdesigned in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6oshows a nanomolar potency for both the 5-HT3 receptor and the human AChE and representsthe first example of a rationally designed high-affinity 5-HT3 receptor ligand showing nanomolarAChE inhibitory activity. Finally, the computational analysis performed on compound 6oallowed the rationalization of the structure−energy determinants for AChE versus BuChEselectivity and revealed the existence of a subsite at the boundary of the 5-HT3 receptorextracellular domain, which could represent a “peripheral” site similar to that evidenced inthe AChE gorge.
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