title: Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists.
abstract: N-Methyl-d-aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over-activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism, and the most promising compound showed an IC50value on the same order of magnitude as that of memantine, an NMDA receptor antagonist in clinical use for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is brain permeable (determined by an in vitro assay) and non-hepatotoxic. All these results indicate that (3S,7aS)-7a-(4-chlorophenyl)-3-(4-hydroxybenzyl)tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (compound 5 b) is a potential candidate for the treatment of pathologies associated with the over-activation of NMDA receptors.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Espadinha
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Dourado
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autonoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain.|Instituto de Investigacion Sanitaria, Hospital, Universitario de la Princesa, 28006, Madrid, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Lajarin-Cuesta
authors.affiliation: Instituto de Química Médica (IQM-CSIC), C/ Juan de la Cierva, 3, 28006, Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Herrera-Arozamena
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Lidia M D
authors.initials: LM
authors.lastname: Gonçalves
authors.affiliation: Instituto de Química Médica (IQM-CSIC), C/ Juan de la Cierva, 3, 28006, Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autonoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain.|Instituto de Investigacion Sanitaria, Hospital, Universitario de la Princesa, 28006, Madrid, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: de Los Rios
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Maria M M
authors.identifier: 0000-0002-2239-9353
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D007769:Lactams; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate
keywords: NMDA receptors; antagonists; asymmetric synthesis; bicyclic lactams; nitrogen heterocycles