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Eur J Med Chem. 2014 May 6;78:10-22. doi: 10.1016/j.ejmech.2014.03.005. Epub 2014 Mar 5.

Solid-supported synthesis, molecular modeling, and biological activity of long-chain arylpiperazine derivatives with cyclic amino acid amide fragments as 5-HT(7) and 5-HT(1A) receptor ligands.

Author information

1
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
2
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
3
Department of Amino Acids, Peptides and Proteins, Institute Biomolecules Max Mousseron, University Montpellier 1, 15 Avenue Charles Flahault, 34-093 Montpellier, France.
4
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: pawel.zajdel@uj.edu.pl.

Abstract

A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (Ki = 18-3134 nM) and 5-HT1A (Ki = 0.5-6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity.

KEYWORDS:

1,2,3,4-Tetrahydroisoquinoline-3-carboxamides; 5-HT(1A) receptor ligands; 5-HT(7) receptor ligands; Hydrogen bonding; Long-chain arylpiperazines; Pipecolic acid; Prolinamides; Solid-phase synthesis

PMID:
24675176
DOI:
10.1016/j.ejmech.2014.03.005
[Indexed for MEDLINE]

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