title: Synthesis of hexahydrocyclopenta[ij]isoquinolines as a new class of dopaminergic agents.
abstract: In this study, we have described the synthesis of the tricyclic 1,2,3,7,8,8a-hexahydrocyclopenta [ij]isoquinoline (HCPIQ). Herein, six differently substituted 5,6-dioxygenated-7-phenyl-HCPIQs have been synthesized using a new methodology via (E)-1-styryl-THIQ by Friedel-Crafts cyclization with Eaton's reagent. Results showed that HCPIQs (3, 3a-e) displayed a moderate affinity for D1 dopamine receptors (DR) in the micromolar range, furthermore the catecholic HCPIQs 3a (NH), 3c (NCH3) and 3e (NCH2CHCH2) exhibited outstanding affinity and high selectivity towards D2 DR. Indeed, 3a, 3c and 3e showed Ki values of 29 nM, 13 nM and 18 nM, respectively, and HCPIQs 3a (NH) and 3c (NCH3) displayed a remarkable selectivity (Ki D1/D2 ratio ∼ 1000-2500). In addition, none of the catecholic compounds showed any cytotoxicity in freshly isolated human neutrophils. Although further studies are needed, these compounds and particularly catecholic HCPIQs, show high potential in the treatment of Parkinson's disease, psychosis or depression.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Laboratorio de Farmacoquímica, Universidad de Valencia, 46100, Vicent Andres Estellés s/n, Burjassot, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Párraga
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Laboratorio de Farmacoquímica, Universidad de Valencia, 46100, Vicent Andres Estellés s/n, Burjassot, Valencia, Spain.
authors.forename: Abraham
authors.initials: A
authors.lastname: Galán
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46013, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Laboratorio de Farmacoquímica, Universidad de Valencia, 46100, Vicent Andres Estellés s/n, Burjassot, Valencia, Spain; Centro de Ecología Química Agrícola-Instituto Agroforestal Mediterraneo, Universidad Politécnica de Valencia (UPV), Campus de Vera s/n, Edificio 6C, 46022, Valencia, Spain. Electronic address: ncabedo@ceqa.upv.es.
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabedo
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Laboratorio de Farmacoquímica, Universidad de Valencia, 46100, Vicent Andres Estellés s/n, Burjassot, Valencia, Spain. Electronic address: dcortes@uv.es.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
mesh_terms: D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000601653:1,2,3,7,8,8a-hexahydrocyclopenta(ij)isoquinoline; D015259:Dopamine Agents; D007546:Isoquinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
keywords: Binding assays; Bischler–Napieralski cyclodehydration; Dopamine receptors; Friedel–Crafts cyclization; Hexahydrocyclopenta[ij]isoquinolines; Tetrahydroisoquinolines