TY - JOUR
T1 - Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050
AU - Shaw, Amanda M.
AU - Boules, Mona
AU - Zhang, Yiqun
AU - Williams, Katrina
AU - Robinson, Jessica
AU - Carlier, Paul R.
AU - Richelson, Elliott
N1 - Funding Information:
This work is supported by the Mayo Foundation for Medical Education and Research.
PY - 2007/1/19
Y1 - 2007/1/19
N2 - Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2′-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2′-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.
AB - Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2′-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2′-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.
KW - Antidepressant
KW - Dopamine
KW - Norepinephrine
KW - Reuptake inhibitor
KW - Serotonin
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U2 - 10.1016/j.ejphar.2006.10.004
DO - 10.1016/j.ejphar.2006.10.004
M3 - Article
C2 - 17109850
AN - SCOPUS:33845804288
SN - 0014-2999
VL - 555
SP - 30
EP - 36
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -