| Reference | 1. IDrugs. 2007 Mar;10(3):193-201.
<br>
Drug evaluation: Vilazodone–a combined SSRI and 5-HT1A partial agonist for the
treatment of depression.
<br>
de Paulis T(1).
<br>
Author information: <br>
(1)[email protected]
<br>
Vilazodone is a combined selective serotonin reuptake inhibitor (SSRI) and a
5-HT(1A) receptor partial agonist that is being developed by Clinical Data Inc
for the treatment of depression. In preclinical studies, vilazodone compared
favorably to other antidepressants such as paroxetine and fluoxetine. Orally
administered vilazodone inhibited ultrasonic vocalization in the rat after
electrical foot shock (a model of anxiolytic activity). Yet, in the forced
swimming test model of depression in rats, vilazodone administered
intraperitoneally was active at 1 mg/kg but not at 3 or 10 mg/kg. During clinical
trials, vilazodone completely abolished REM sleep for 8 h and demonstrated
antidepressant efficacy that was equal to that of current antidepressant
therapeutics. The author concludes that the success of vilazodone as an effective
antidepressant agent will depend on whether the drug can produce a more rapid
antidepressant effect than other SSRI agents, or if specific genetic markers of
patients can be associated with clinical efficacy.
<br>
2. Eur J Pharmacol. 2005 Mar 7;510(1-2):49-57.
<br>
Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin
reuptake inhibitor, vilazodone.
<br>
Hughes ZA(1), Starr KR, Langmead CJ, Hill M, Bartoszyk GD, Hagan JJ, Middlemiss
DN, Dawson LA.
<br>
Author information: <br>
(1)Neuropharmacology Research, Psychiatry CEDD, Glaxo Smith Kline, New Frontiers
Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
<br>
Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT)
reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS binding
in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic
activity comparable to the 5-HT1A receptor agonist
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.)
dose-dependently displaced in vivo [3H]DASB
(N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex
and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo.
Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause
a 2-fold increase in extracellular 5-HT but no change in noradrenaline or
dopamine levels in frontal cortex of freely moving rats. In contrast,
administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with
a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.),
produced no increase in cortical 5-HT whilst increasing noradrenaline and
dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT
levels (but no change in noradrenaline or dopamine levels) was observed after
combination of the 5-HT(1A) receptor antagonist,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamid
e) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary,
vilazodone behaved as a high efficacy partial agonist at the rat hippocampal
5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo
vilazodone induced a selective increase in extracellular levels of 5-HT in the
rat frontal cortex. This profile was similar to that seen with a 5-HT1A receptor
antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in
combination with paroxetine.
<br>
3. Bioorg Med Chem Lett. 2004 May 17;14(10):2681-4.
<br>
A new synthesis of indole 5-carboxylic acids and 6-hydroxy-indole-5-carboxylic
acids in the preparation of an o-hydroxylated metabolite of vilazodone.
<br>
Heinrich T(1), Böttcher H.
<br>
Author information: <br>
(1)Merck KGaA, Preclinical Pharmaceutical Research, Frankfurter Str. 250, 64293
Darmstadt, Germany. [email protected]
<br>
A major metabolite of the potential antidepressant vilazodone formed in rat, dog,
monkey and human liver microsomes is the 5-cyano-6-hydroxy-1H-indole derivative.
For the construction of the salicyl-like substituted indole we adapted a
synthesis of carmoxirole using Japp-Klingemann type Fischer-indole synthesis
protocols. Functional group interconversion of carboxylic acid via carboxamide
into cyanide was performed with methanesulfonic acid chloride.
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