Molecules2016，Vol.21Issue(4) ：22.DOI:10.3390/molecules21040433

Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls

Strekowski, Lucjan Saczewski, Jaroslaw Raux, Elizabeth A. Fernando, Nilmi T. Klenc, Jeff Paranjpe, Shirish Raszkiewicz, Aldona Blake, Ava L. Ehalt, Adam J. Barnes, Samuel Baranowski, Timothy C. Sullivan, Shannon M. Satala, Grzegorz Bojarski, Andrzej J.
Molecules2016，Vol.21Issue(4) ：22.DOI:10.3390/molecules21040433
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Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls

Strekowski, Lucjan 1Saczewski, Jaroslaw 2Raux, Elizabeth A. 1Fernando, Nilmi T. 1Klenc, Jeff 1Paranjpe, Shirish 1Raszkiewicz, Aldona 1Blake, Ava L. 1Ehalt, Adam J. 1Barnes, Samuel 1Baranowski, Timothy C. 1Sullivan, Shannon M. 1Satala, Grzegorz 3Bojarski, Andrzej J.3
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作者信息

  • 1. Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA
  • 2. Med Acad Gdansk, Dept Chem Technol Drugs, Aleja Generala Jozefa Hallera 107, PL-80416 Gdansk, Poland
  • 3. Polish Acad Sci, Inst Pharmacol, Dept Med Chem, Smetna 12, PL-31343 Krakow, Poland
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Abstract

A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl) pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7/5-HT2AR ligand, and 13 as a multi-receptor (5-HT7, 5-HT2A, 5-HT6 and D-2) agent.

Key words

5-HT7 receptor ligands/5-HT/serotonin/synthesis/structure-affinity relationships (SAR)/N-methylpiperazine/3-furyl

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出版年

2016
Molecules

Molecules

SCI
ISSN：1420-3049
被引量4
参考文献量36
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