title: 3-Chlorotyramine Acting as Ligand of the D2 Dopamine Receptor. Molecular Modeling, Synthesis and D2 Receptor Affinity.
abstract: We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2 -DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2 -DR to that reported for DA.
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biologicas (IMIBIO-SL -CONICET), Chacabuco 915, 5700 San Luis, Argentina phone: (54) 2652.423789.|Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Química, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste, Avda. Libertad 5460, (3400) Corrientes, Argentina.
authors.forename: Emilio
authors.initials: E
authors.lastname: Angelina
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biologicas (IMIBIO-SL -CONICET), Chacabuco 915, 5700 San Luis, Argentina phone: (54) 2652.423789. saanduja@unsl.edu.ar.|Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina. saanduja@unsl.edu.ar.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Andujar
authors.affiliation: Departamento de Farmacología, Laboratorio de Fármacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, España.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biologicas (IMIBIO-SL -CONICET), Chacabuco 915, 5700 San Luis, Argentina phone: (54) 2652.423789.|Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garibotto
authors.affiliation: Departamento de Farmacología, Laboratorio de Fármacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, España.
authors.forename: Javier
authors.initials: J
authors.lastname: Párraga
authors.affiliation: Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Química, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste, Avda. Libertad 5460, (3400) Corrientes, Argentina.
authors.forename: Nelida
authors.initials: N
authors.lastname: Peruchena
authors.affiliation: Centro de Ecología Química Agrícola-Instituto Agroforestal Mediterráneo, Universidad Politécnica de Valencia, Campus de Vera, Edificio 6C, 46022 Valencia, España.
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabedo
authors.affiliation: Instituto de Química Orgánica, Facultad de Bioquímica Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, S. M. de Tucumán, T4000INI. Argentina.
authors.forename: Margarita
authors.initials: M
authors.lastname: Villecco
authors.affiliation: Departamento de Farmacología, Laboratorio de Fármacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, España.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biologicas (IMIBIO-SL -CONICET), Chacabuco 915, 5700 San Luis, Argentina phone: (54) 2652.423789.|Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina.
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Enriz
mesh_terms: D065127:Dopamine D2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism; D014439:Tyramine / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D006843:Hydrocarbons, Chlorinated; D017448:Receptors, Dopamine D2; D014439:Tyramine
keywords: 3-Chlorotyramine; D2 dopamine receptor; MD simulations; QTAIM analysis