title: Synthesis and Structure-Activity Relationship Analysis of 5-HT₇ Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls.
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.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. lucjan@gsu.edu.
authors.forename: Lucjan
authors.initials: L
authors.lastname: Strekowski
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Aleja Generała Józefa Hallera 107, Gdańsk 80-416, Poland. js@gumed.edu.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sączewski
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. earaux@gmail.com.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raux
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. fernando.nilmi@gmail.com.
authors.forename: Nilmi T
authors.initials: NT
authors.lastname: Fernando
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. jklenc@merchantgould.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Klenc
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. shirishp007@gmail.com.
authors.forename: Shirish
authors.initials: S
authors.lastname: Paranjpe
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. aldona.paluchowska@urpl.gov.pl.
authors.forename: Aldona
authors.initials: A
authors.lastname: Raszkiewicz
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. ablake@bakerlaw.com.
authors.forename: Ava L
authors.initials: AL
authors.lastname: Blake
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. adamehalt@gmail.com.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ehalt
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. sambarnes2@gmail.com.
authors.forename: Samuel
authors.initials: S
authors.lastname: Barnes
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. tcb@bellsouth.net.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Baranowski
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, GA 30302, USA. ssullivan@yahoo.com.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Sullivan
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland. satala@if-pan.krakow.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland. bojarski@if-pan.krakow.pl.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
mesh_terms: D006801:Humans; D008024:Ligands; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D011985:Receptors, Serotonin / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D000077489:Piperazine; C030986:pyrimidine
keywords: 3-furyl; 5-HT; 5-HT7 receptor ligands; N-methylpiperazine; serotonin; structure-affinity relationships (SAR); synthesis