title: Identification of a new selective dopamine D4 receptor ligand.
abstract: The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4=0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4=3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki <100 nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Dinithia
authors.initials: D
authors.lastname: Sampson
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Xue Y
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Suresh V K
authors.initials: SV
authors.lastname: Eyunni
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Jagan R
authors.initials: JR
authors.lastname: Etukala
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Ofori
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bricker
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
authors.forename: Nazarius S
authors.initials: NS
authors.lastname: Lamango
authors.affiliation: Department of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, NC 27599, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.affiliation: Department of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, NC 27599, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA. Electronic address: seth.ablordeppey@famu.edu.
authors.forename: Seth Y
authors.initials: SY
authors.lastname: Ablordeppey
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008024:Ligands; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000600993:(E)-3-(1H-Indol-3-yl)-N-(2,4,6-trimethoxyphenyl)acrylamide; D000178:Acrylamides; D018492:Dopamine Antagonists; D007211:Indoles; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B; D017448:Receptors, Dopamine D2; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4
keywords: Aryl piperazine; Benzofuran; Benzothiazole; Benzoxazole; D(4) ligand; D(4) selective ligand; Phenyl piperazine