Next Article in Journal
Photophysical Characterization and in Vitro Phototoxicity Evaluation of 5,10,15,20-Tetra(quinolin-2-yl)porphyrin as a Potential Sensitizer for Photodynamic Therapy
Previous Article in Journal
sym-Trisubstituted 1,3,5-Triazine Derivatives as Promising Organic Corrosion Inhibitors for Steel in Acidic Solution
Article Menu
Issue 4 (April) cover image

Export Article

Open AccessArticle
Molecules 2016, 21(4), 433; doi:10.3390/molecules21040433

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

1
Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA
2
Department of Chemical Technology of Drugs, Medical University of Gdańsk, Aleja Generała Józefa Hallera 107, Gdańsk 80-416, Poland
3
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 27 February 2016 / Revised: 16 March 2016 / Accepted: 22 March 2016 / Published: 31 March 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [5537 KB, uploaded 31 March 2016]   |  

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 D2) agent. View Full-Text
Keywords: 5-HT7 receptor ligands; 5-HT; serotonin; synthesis; structure-affinity relationships (SAR); N-methylpiperazine; 3-furyl 5-HT7 receptor ligands; 5-HT; serotonin; synthesis; structure-affinity relationships (SAR); N-methylpiperazine; 3-furyl
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Strekowski, L.; Sączewski, J.; Raux, E.A.; Fernando, N.T.; Klenc, J.; Paranjpe, S.; Raszkiewicz, A.; Blake, A.L.; Ehalt, A.J.; Barnes, S.; Baranowski, T.C.; Sullivan, S.M.; Satała, G.; Bojarski, A.J. Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls. Molecules 2016, 21, 433.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top