title: Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.
abstract: The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.
authors.affiliation: Drug Discovery and Preclinical Development, Esteve, Baldiri Reixach 4-8, 08028 Barcelona, Spain. jldiaz@esteve.es
authors.forename: José Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: Ute
authors.initials: U
authors.lastname: Christmann
authors.forename: Ariadna
authors.initials: A
authors.lastname: Fernández
authors.forename: Mónica
authors.initials: M
authors.lastname: Luengo
authors.forename: Magda
authors.initials: M
authors.lastname: Bordas
authors.forename: Raquel
authors.initials: R
authors.lastname: Enrech
authors.forename: Mónica
authors.initials: M
authors.lastname: Carro
authors.forename: Rosalia
authors.initials: R
authors.lastname: Pascual
authors.forename: Javier
authors.initials: J
authors.lastname: Burgueño
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Jordi
authors.initials: J
authors.lastname: Benet-Buchholz
authors.forename: Jordi
authors.initials: J
authors.lastname: Cerón-Bertran
authors.forename: Jesús
authors.initials: J
authors.lastname: Ramírez
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Reinoso
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Fernández de Henestrosa
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Carmen
authors.initials: C
authors.lastname: Almansa
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D055598:Chemical Phenomena; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D008024:Ligands; D011804:Quinolines; D017480:Receptors, sigma