Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (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-HT3 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 6o 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.

Further studies on the interaction of the 5-hydroxytryptamine(3) (5-HT3) receptor with arylpiperazine ligands. Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties / A., Cappelli; A., Gallelli; M., Manini; M., Anzini; L., Mennuni; F., Makovec; Menziani, Maria Cristina; S., Alcaro; F., Ortuso; S., Vomero. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 48(2005), pp. 3564-3575.

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