title: A novel spirocyclic tropanyl-Δ²-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake.
abstract: A group of spirocyclic tropanyl-Δ(2)-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrile oxides to olefins. Their interaction with the dopamine and serotonin transporters (DAT and SERT, respectively) was evaluated through binding experiments. The majority of the compounds had no inhibitory effects (IC(50) >> 10 μM), while some had an IC(50) value in the range 5-10 μM (8a-c, 10b and 11c on DAT, 12b on SERT). Unexpectedly, one of the tertiary amines under investigation, that is 3'-methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5'(4'H)-isoxazole 7a, was able to enhance at a concentration of 10 μM both [(3)H]citalopram and [(3)H]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of B(max)) and [(3)H]serotonin uptake (up to 30%) in cortical synaptosomes. This peculiar pharmacological profile of 7a suggests it binds to an allosteric site on SERT, and positions derivative 7a as a very useful tool to investigate SERT machinery.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. clelia.dallanoce@unimi.it
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000737:chemistry / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017374:Paroxetine / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000737:chemistry / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D007555:Isoxazoles; D050486:Serotonin Plasma Membrane Transport Proteins; D013141:Spiro Compounds; C579452:tropanyl-delta2-isoxazoline; D015283:Citalopram; D012701:Serotonin; D017374:Paroxetine