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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2005-5-12
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3564-75
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:15887964-Acetylcholinesterase,
pubmed-meshheading:15887964-Acridines,
pubmed-meshheading:15887964-Animals,
pubmed-meshheading:15887964-Binding Sites,
pubmed-meshheading:15887964-Butyrylcholinesterase,
pubmed-meshheading:15887964-Cerebral Cortex,
pubmed-meshheading:15887964-Cholinesterase Inhibitors,
pubmed-meshheading:15887964-Computer Simulation,
pubmed-meshheading:15887964-Humans,
pubmed-meshheading:15887964-Ligands,
pubmed-meshheading:15887964-Male,
pubmed-meshheading:15887964-Models, Molecular,
pubmed-meshheading:15887964-Molecular Conformation,
pubmed-meshheading:15887964-Piperazines,
pubmed-meshheading:15887964-Quinolines,
pubmed-meshheading:15887964-Radioligand Assay,
pubmed-meshheading:15887964-Rats,
pubmed-meshheading:15887964-Rats, Wistar,
pubmed-meshheading:15887964-Receptors, Serotonin, 5-HT3,
pubmed-meshheading:15887964-Structure-Activity Relationship,
pubmed-meshheading:15887964-Thermodynamics
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pubmed:year |
2005
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pubmed:articleTitle |
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.
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pubmed: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
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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