875585-54-9Relevant academic research and scientific papers
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
Cappelli, Andrea,Gallelli, Andrea,Manini, Monica,Anzini, Maurizio,Mennuni, Laura,Makovec, Francesco,Menziani, M. Cristina,Alcaro, Stefano,Ortuso, Francesco,Vomero, Salvatore
, p. 3564 - 3575 (2005)
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 Ki 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.
