title: Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors.
abstract: Syntheses were undertaken of derivatives of (2S,4R)-(-)-trans-4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N,N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([-]-trans>[+]-trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4'-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S,4R]-[+]-trans>[2S,4R]-[-]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4'-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4'-Cl)-PAT and (-)-trans-4-(3'-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding ('binge-eating').
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sakhuja
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Krishnakanth
authors.initials: K
authors.lastname: Kondabolu
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115-5000, United States.
authors.forename: Tania
authors.initials: T
authors.lastname: Córdova-Sintjago
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Travers
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Vincek
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Myong Sang
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Khalil A
authors.initials: KA
authors.lastname: Abboud
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115-5000, United States.
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Canal
authors.affiliation: Department of Medicinal Chemistry and Department of Chemistry, University of Florida, Gainesville, FL 32610-0485, United States; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115-5000, United States. Electronic address: ra.booth@neu.edu.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive / Q000502:physiology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009281:Naphthalenes; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D044348:Receptors, Serotonin, 5-HT2
keywords: 5-HT(2); Aminotetralin; Histamine H(1); Molecular modeling; Serotonin receptors; X-ray crystal structure