Posted by jrbecker on December 12, 2005, at 10:18:41
In reply to Valdoxan vs Rozerem - nearly identical - ADsleep, posted by lunesta on December 12, 2005, at 7:12:12
> Apparently both of these drugs have nearly the exact same binding profile for the melatonergic system at the MT1 and MT2 receptors as agonists.
>
> What is interesting is that Valdoxan is being studied and almost done with trials in Europe for depression with very unique and good results, with nearly no side effects, while at the same time, the drug Rozerem, just approved and out in the USA is being used for insomnia rather than depression.
>
> They both work on the same exact receptors, with nearly the same affinity.
>
> So here is the cool thing, there is studies on pubmed.com suggesting that Rozerem shows antidepressant action as well.
>
> The key difference though may be the dosing, , as well as the "nearly" identical, but not 100% identical binding sites, some of which may not yet be identified for Valdoxan, making it more antidepressant like, than Rozerem.
>
> What I am suggesting is that Rozerem may have significant antidepressant properties equivalent to Valdoxan (not out yet) and that it may be worth trying off label or in higher dosages for depression and/or sleep disorder.
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> Usually sleep/depression/cycidian rythm disturbance is messed up in depression, so you may see how both drugs could actually help sleep and depression.
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> Rozerem is currently available, as a non controlled substance for insomnia in the USA.
>
> I would like to hear of anyones experience with it for, insomnia, sleep onset, or depression relief as a side effect.
>
> Thanks
> lunestaas scott mentioned above, rozerem (ramelteon) is not identical in its pharmacological actions to valdoxan (agomelatine). although they are both melatonergic agonists with a short-half life, the key difference is that agomelatine is also a potent 5-HT2C antagonist. Studies have revealed that its >primary< antidepressant mechanism is via this receptor's inactivation....
Psychopharmacology (2005) 177: 1–12
Mark J. Millan . Mauricette Brocco . Alain Gobert .Anne Dekeyne
Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade
Abstract Rationale: The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)2C receptors. Objectives: To determine whether, by virtue of its antagonist
properties at 5-HT2C receptors, agomelatine elicits anxiolytic properties in rats. Methods: Employing a combined neurochemical and behavioural approach, actions of agomelatine were compared to those of melatonin, the selective 5-HT2C receptor antagonist, SB243,213, and the benzodiazepine, clorazepate. Results: In unfamiliar pairs of rats exposed to a novel
environment, agomelatine enhanced the time devoted to active social interaction, an action mimicked by clorazepate and by SB243,213. In a Vogel conflict procedure, agomelatine likewise displayed dose-dependent anxiolytic activity with a maximal effect comparable to clorazepate,
and SB243,213 was similarly active in this procedure. In a plus-maze procedure in which clorazepate significantly enhanced percentage entries into open arms, agomelatine revealed only modest activity and SB243,213 was inactive. Further, like SB243,213, and in contrast to clorazepate, agomelatine did not suppress ultrasonic vocalizations emitted by rats re-exposed to an environment associated with an aversive stimulus. Whereas clorazepate
reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and
elevated those of noradrenaline. SB243,213 acted similarly to agomelatine. Melatonin, which did not modify extracellular levels of 5-HT or noradrenaline, was ineffective in all models of anxiolytic activity. Furthermore,
the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests. Conclusions: In contrast to melatonin, and reflecting blockade of 5-HT2C receptors, agomelatine is active in several models of anxiolytic properties in rodents. The
anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on corticolimbic monoaminergic pathways.
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 306, No. 3M. J. MILLAN, A. GOBERT, F. LEJEUNE, A. DEKEYNE, A. NEWMAN-TANCREDI, V. PASTEAU, J.-M. RIVET, and
D. CUSSACThe Novel Melatonin Agonist Agomelatine (S20098) Is an Antagonist at 5-Hydroxytryptamine2C Receptors, Blockade of Which Enhances the Activity of Frontocortical Dopaminergic
and Adrenergic PathwaysABSTRACT
Agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native(porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors,
respectively. It also interacted with h5-HT2B receptors(6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (_5.0/5.3) and 5-HT1A (_5.0/5.2) receptors, and negligible
(_5.0) affinity for other 5-HT receptors. In antibody capture/scintillation proximity assays, agomelatine concentration dependently
and competitively abolished h5-HT2C receptor-mediated activation of Gq/11 and Gi3 (pA2 values of 6.0 and 6.1). As measured by [3H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT2C (pKB value of 6.1)and h5-HT2B (pKB value of 6.6) receptors. In vivo, it dose dependently
blocked induction of penile erections by the 5-HT2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[
a]inden-3-yl) ethylamine (Ro60,0332). Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in
frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity
of ventrotegmental dopaminergic neurons was unaffected by agomelatine, it abolished their inhibition by Ro60,0175. Extracellular
levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus
coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-
ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely reflect blockade of 5-HT2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, in distinction to agomelatine, melatonin showed negligible activity at
5-HT2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2B and 5-HT2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.
poster:jrbecker
thread:588289
URL: http://www.dr-bob.org/babble/20051211/msgs/588311.html