4 replies to this topic

[playground]

I am particularly interested by the promise that Flesinoxan has shown during preliminary trials

for it's anti-depressant and anxiolytic properties.   Flesinoxan is a 5HT1A agonist.

 

See here:  https://en.wikipedia...wiki/Flesinoxan

 

Despite this drug's good tolerability and therapeutic promise this drug was abandonned

due to 'management decisions'.    There is no patent out on this drug.

 

Does anyone have any suggestions for how and where i might find a source for this drug

 

Thanks to anyone that responds.

 

 

[Area-1255]

A lot of drugs get dropped not because of their efficacy but because of marketing applications - the drugs have to be able to be introduced in a way that would be appealing to those selling them and the consumers ..but additionally, the miscellaneous biological actions and other molecular factors such as half-life, oral bioavailability and such would have to be considered to make it practical.

 

Another example is the almost-made-true designated Alzheimer's drug 'Lecozotan' - it is chemically opposite to Flesinoxan as it's a 1A antagonist - which is proposed to be beneficial to memory and LTP and can ameliorate scopolamine related and NMDAR blockade related memory impairment.

 

The other thing is there is a lot of debate on 5-HT1A ligands; not to mention there are already several on the market that are readily available; like buspirone etc

but additionally, the science is not so linear as to depict an agonist as universally advantageous over an antagonist...and both agonists and antagonist show benefits..not just in the realm of memory but as well in depression...antagonists may also help depression.

 

 

 

Acute lecozotan administration increases learning and memory in rats without affecting anxiety or behavioral depression

 

Laboratory of Cellular Physiology, Medical School, University Centroccidental Lisandro Alvarado, Barquisimeto, 3001-A, Venezuela.

Pharmacology Biochemistry and Behavior (Impact Factor: 2.82). 02/2010; 95(3):325-30. DOI: 10.1016/j.pbb.2010.02.008

Source: PubMed

ABSTRACT Lecozotan is a selective serotonergic 5-HT(1A) receptor antagonist previously shown to enhance task performance efficiency in aged rhesus monkeys. In the present report we tested the ability of this drug to modify memory and learning in rats during a modified passive avoidance response test, and also tested its effect on anxiety with the elevated plus maze, and behavioral depression in the inescapable swim test. Lecozotan enhanced memory in a dose-dependent manner (0, 0.3, 0.5, 1 and 2mg/kg; s.c.), or prevented memory impairment previously induced with scopolamine-HCl. No significant changes in anxiety and behavioral depression were detected in animals treated with different doses of lecozotan (0, 0.3, 1 and 2mg/kg; s.c.) compared to control animals. These results suggest that lecozotan could enhance learning and memory in animals without affecting anxiety or behavioral depression scores and that it could be a viable alternative in the treatment of patients with cognitive deficits such as the Alzheimer's disease.

Acute lecozotan administration increases learning and memory in rats without affecting anxiety or behavioral depression - ResearchGate. Available from: http://www.researchg...oral_depression [accessed Sep 9, 2015].

 

 

 

Lecozotan (SRA-333): A Selective Serotonin 1A Receptor Antagonist That Enhances the Stimulated Release of Glutamate and Acetylcholine in the Hippocampus and Possesses Cognitive-Enhancing Properties

 

 

Knocking 5-HT1A down to bring mood up

 

Edited by Area-1255, 09 September 2015 - 04:22 PM.

[playground]

excellent post.  Thanks :-)

[playground]

I'm quite interested by the suggestion that 5HT1A receptor agonists work differentially for males and females.

As i understand it, 5HT1A agonists have a pro-sexual effect on females, but the story is more mixed for males.

 

I suppose it just offers experimental data to confirm what many men have thought for.... well,  presumably millennia.  

Women's brains are wired up very differently to men's  (no judgement implied or intended)

[Area-1255]

I'm quite interested by the suggestion that 5HT1A receptor agonists work differentially for males and females.

As i understand it, 5HT1A agonists have a pro-sexual effect on females, but the story is more mixed for males.

 

I suppose it just offers experimental data to confirm what many men have thought for.... well,  presumably millennia.  

Women's brains are wired up very differently to men's  (no judgement implied or intended)

Yes; I wrote a whole thread on this. 

But it's very complex.

5-HT1A agonists tend to increase risk of premature ejaculation but ironically also weaken/abolish erectile capacity...

Until the receptor gets desensitized from pounding it with agonists for a while, of course. 

Then while the person in theory feels less depressed - they also feel asexual...for women it may not be the case.

 

The hard part, is understanding how it relates to psychology..for example, 1A agonists tend to decrease anxiety before the receptor is de-sensitized...but also increase oxytocin release...which also seems to come from the 'autoreceptors' indicating that serotonin being decreased leads to oxytocin release...this makes sense as those 'in love' tend to have less serotonin and more dopamine and PEA.

 

My research and conclusions is that it really depends on the person..the other issue is while antagonists to the 1A receptor may increase erectile function...I doubt they would have a direct effect on libido...they may increase olfactory sensory inputs though, making you more sensitive to female pheromones.

 

For men, sympathetic nervous system activity can not be excessive, and typically should be on the lower end of activity and EPSC's/electrical impulses - otherwise no arousal will occur. For women, sympathetic discharge/nervous system impulses act a little differently...since females have more estrogen - they seem to be somewhat altered in their responses to adrenaline. 

 

However, both high and low estrogen in both men and women seems to distort general cognitive and motivational outputs.

 

The trick is knowing yourself - if you feel you have a sympathetic nervous overload or are hyper-adrenaline like  state..then one should probably not touch any ligands for the receptor...or trend towards an agonist...although buspirone and other 1A agonists have been shown to increase frontal-cortical noradrenaline release...so the Irony is the effects of agonists vary either way.

 

 

 

Psychoneuroendocrinology. 2002 Jul;27(5):609-18.

Involvement of the 5-HT(1A) and 5-HT(1B) serotonergic receptor subtypes in sexual arousal in male mice.

Popova NK1, Amstislavskaya TG.

Author information

 

Abstract

The presence of a sexually receptive female behind a partition that prevents physical contact, but not seeing or smelling, increases blood testosterone level and induces the specific behavior in CBA male mice so that they more frequently approach the partition and spend more time near it in an attempt to make their way to the female. Treatment with the selective 5-HT(1A) serotonin receptor agonist 8-OH-DPAT (0.1, 0.25, 0.5 and 2.0 mg/kg) induced a dose-dependent decrease in the amount of time spent by the males near the partition, or "partition time", which is considered the main pattern of sexual motivation. The activating effect of female exposure on the male's pituitary-testicular system was totally blocked, as no increase in plasma testosterone level was observed. The 5-HT(1A) antagonist p-MPPI (0.1, 0.2 and 0.4 mg/kg) itself did not affect behavior or alter plasma testosterone, but attenuated the inhibiting effect of 8-OH-DPAT on behavior and totally antagonised the effect of the 5-HT(1A) agonist on testosterone response. The 5-HT(1B) agonist CGS-12066A (1.0 and 2.0 mg/kg) has no influence on the plasma testosterone increase exhibited by the male in response to female exposure. At the same time, either dose of CGS-12066A significantly reduced the partition time. The conclusion was made that the 5-HT(1A) subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT(1B) receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.

PMID:   11965359   [PubMed - indexed for MEDLINE]