TY - JOUR
T1 - Synthesis and structure-activity relationship analysis of 5-HT7 receptor antagonists
T2 - Piperazin-1-yl substituted unfused heterobiaryls
AU - Strekowski, Lucjan
AU - Saczewski, Jarosław
AU - Raux, Elizabeth A.
AU - Fernando, Nilmi T.
AU - Klenc, Jeff
AU - Paranjpe, Shirish
AU - Raszkiewicz, Aldona
AU - Blake, Ava L.
AU - Ehalt, Adam J.
AU - Barnes, Samuel
AU - Baranowski, Timothy C.
AU - Sullivan, Shannon M.
AU - Satała, Grzegorz
AU - Bojarski, Andrzej J.
N1 - Publisher Copyright:
© 2016 by the authors;.
PY - 2016/4
Y1 - 2016/4
N2 - 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-HT2A R ligand, and 13 as a multi-receptor (5-HT7 , 5-HT2A , 5-HT6 and D2 ) agent.
AB - 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-HT2A R ligand, and 13 as a multi-receptor (5-HT7 , 5-HT2A , 5-HT6 and D2 ) agent.
KW - 3-furyl
KW - 5-HT
KW - 5-HT receptor ligands
KW - N-methylpiperazine
KW - Serotonin
KW - Structure-affinity relationships (SAR)
KW - Synthesis
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U2 - 10.3390/molecules21040433
DO - 10.3390/molecules21040433
M3 - Article
C2 - 27043518
AN - SCOPUS:84966762454
SN - 1420-3049
VL - 21
JO - Molecules
JF - Molecules
IS - 4
M1 - 433
ER -