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. 2012 Nov 12;4(1):46-51.
doi: 10.1021/ml300262e. eCollection 2013 Jan 10.

Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity

Dean G Brown  1 , Peter R Bernstein  1 , Ye Wu  1 , Rebecca A Urbanek  1 , Christopher W Becker  1 , Scott R Throner  1 , Bruce T Dembofsky  1 , Gary B Steelman  1 , Lois A Lazor  1 , Clay W Scott  1 , Michael W Wood  1 , Steven S Wesolowski  1 , David A Nugiel  1 , Stephanie Koch  1 , Jian Yu  1 , Donald E Pivonka  1 , Shuang Li  1 , Carol Thompson  1 , Anna Zacco  1 , Charles S Elmore  1 , Patricia Schroeder  1 , JianWei Liu  1 , Christopher A Hurley  2 , Stuart Ward  2 , Hazel J Hunt  2 , Karen Williams  2 , Joseph McLaughlin  1 , Valerie Hoesch  1 , Simon Sydserff  1 , Donna Maier  1 , David Aharony  1
Affiliations

Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity

Dean G Brown et al. ACS Med Chem Lett. .

Abstract

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.

Keywords: antidepressant; dopamine; norepinephrine; uptake inhibitors.

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Figures

Figure 1
Figure 1
Examples of SSRI, SNRI, NDRI, and TRI.
Scheme 1
Scheme 1. Preparation of Azepine Analogues
Reagents and conditions: (a) CH=CHCH2NHMe, 2-chloro-1-methyl pyridinium iodide, CH2Cl2, 25–85%. (b) Grubbs II catalyst,, PhMe, 40 °C, 40–70%. (c) LiAlH4, THF, 20–75%. (d) ACE-Cl, PhMe, reflux, 30–62%.
Scheme 2
Scheme 2. Preparation of Azepine and Azepane Analogues
Reagents and conditions: (a) 7a, H2, Pd/C, HCl, 79%. (b) 8a, PtO2, H2, AcOH. (c) KOH, MeCN/H20, 150 °C, microwave, 75% for 11, 35% for 12.
Scheme 3
Scheme 3. Quaternary Substituted Analogues
Reagents and conditions: (a) BrCH2CH2OMOM, NaH, THF, 42%. (b) CH=CHCH2Br, KOH, TBAI, MeCN, 77%. (c) DIBAL-H, PhMe. (d) CH=CHCH2NH2, NaBH(OAc)3, 1,2-dichloroethane, 37% for steps c and d. (e) Boc2O, CH2Cl2, 78%. (f) Grubbs II catalyst, CH2Cl2, reflux, quan. (g) HCl, MeOH, quan., chiral SFC.
Scheme 4
Scheme 4. Quaternary Substituted Piperidines
Reagents and conditions: (a) NaH, Br(CH2)2OMOM. (b) NaH, Br(CH2)3Cl. (c) Ra Ni, NH4OH, NaCl (aq); HCl, MeOH; chiral HPLC.
Figure 2
Figure 2
In vivo activity in FST, spontaneous LMA. Top row: Immobility time in FST for compounds 3, 8b, and 21a following dosing (sc) in Sprague–Dawley rats. Middle row: Distance traveled in spontaneous locomotive activity (LMA) in rats as measured by beam breaks. Bottom row: Stereotypic behavior in the locomotive activity assay as measured by number of times the same beam is broken. DMI = desipramine (positive control, dosed 15 mg/kg ip). Data presented as group means ± SEMs. An asterisk indicates statistical significance from vehicle (Veh), using one-way ANOVA analysis.
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