title: Expanding the multipotent profile of huprine-tacrine heterodimers as disease-modifying anti-Alzheimer agents.
abstract: BACKGROUND
  Multifactorial diseases such as Alzheimer's disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely β-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity.
  
  
  OBJECTIVE
  In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M(1) receptors as well as their neuroprotective effects against an oxidative insult.
  
  
  METHODS
  Sprague-Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [(3)H]pirenzepine (for M(1) receptors) or 0.8 nM [(3)H]quinuclidinyl benzilate (for M(2) receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 μM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers.
  
  
  RESULTS
  A low nanomolar affinity and M(1)/M(2) selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 μM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 μM.
  
  
  CONCLUSIONS
  Even though it remains to be determined if these compounds act as agonists at M(1) receptors, as it is the case of the parent huprine Y, their low nanomolar M(1) affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents.
authors.affiliation: Laboratori de Química Farmacèutica, Unitat Associada al CSIC, Facultat de Farmàcia, and Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
authors.forename: Marta
authors.initials: M
authors.lastname: Pera
authors.forename: Júlia
authors.initials: J
authors.lastname: Relat
authors.forename: Míriam
authors.initials: M
authors.lastname: Ratia
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.forename: Xavier
authors.initials: X
authors.lastname: Formosa
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Albert
authors.initials: A
authors.lastname: Badia
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010890:Pirenzepine / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology*; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D006576:Heterocyclic Compounds, 4 or More Rings; D018727:Muscarinic Antagonists; C404519:huprine Y; D014316:Tritium; D010890:Pirenzepine; D013619:Tacrine; D011813:Quinuclidinyl Benzilate; D006861:Hydrogen Peroxide