title: 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.
abstract: Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT(3)) receptor. Most of the new compounds show subnanomolar 5-HT(3) 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 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-HT(3) receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT(3) 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-HT(3) receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Gallelli
authors.forename: Monica
authors.initials: M
authors.lastname: Manini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Menziani
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C500839:3-methyl-2-(4-methyl-1-piperazinyl)-N-(7-((1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)quinoline-4-carboxamide; D000166:Acridines; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010879:Piperazines; D011804:Quinolines; D044406:Receptors, Serotonin, 5-HT3; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase