Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls
AbstractA 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
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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.
Strekowski L, Sączewski J, Raux EA, Fernando NT, Klenc J, Paranjpe S, Raszkiewicz A, Blake AL, Ehalt AJ, Barnes S, Baranowski TC, Sullivan SM, Satała G, Bojarski AJ. Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls. Molecules. 2016; 21(4):433.Chicago/Turabian Style
Strekowski, Lucjan; Sączewski, Jarosław; 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.; Satała, Grzegorz; Bojarski, Andrzej J. 2016. "Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls." Molecules 21, no. 4: 433.
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