Yohimbine vs Alpha Yohimbine (rauwolscine)

[JudoJosh]

Which is more effective?


Alpha-y is touted as having less side effects but my question is, is it more effective?


My understanding is both alpha-y and y antagonize the alpha 2-adrenoceptors but y will also antagonize the alpha 1-adrenoceptors too which can hinder lipoysis and alpha-y will not (or at least not as much as y would.

[3H]rauwolscine (alpha-yohimbine): a specific antagonist radioligand for brain alpha 2-adrenergic receptors.


Abstract
[3H]Rauwolscine, a specific and potent alpha 2-antagonist radioligand, was used to characterize alpha 2-receptor binding in bovine cerebral cortex. [3H]Rauwolscine binding was reversible, stereospecific, and saturable. Association, dissociation, and saturation studies revealed one site interactions (k -1/k+1 = 1.2 nM, KD = 2.5 nM, Bmax = 160 fmol/mg protein) and competition studies indicated that [3H]rauwolscine labeled the alpha 2-receptor. Agonists inhibited [3H]rauwolscine binding in a shallow, GTP-sensitive manner. These results suggest that [3H]rauwolscine specifically labels both the high and low affinity states of the alpha 2-receptor in brain membranes.


PMID 6276200

In vivo alpha(1)-adrenergic lipolytic activity in subcutaneous adipose tissue of obese subjects.


The role of alpha(1)-adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in severely obese subjects. The lipolysis rate was assessed by determination of interstitial glycerol concentration. The alpha(1)-adrenoceptor agonist norfenefrine caused an increase in glycerol level in adipose tissue that was similar to that observed with the physiologic alpha(1,2)-beta(1)-adrenoceptor agonist norepinephrine, whereas the alpha(1)-adrenoceptor antagonist urapidil showed no effect on basal lipolysis rate. However, the enhanced glycerol concentration due to norfenefrine and norepinephrine was suppressed in the presence of urapidil. The beta-adrenoceptor antagonist propranolol showed no effect on norfenefrine-stimulated glycerol outflow. Blood flow was assessed using the ethanol escape technique. Perfusion with norfenefrine decreased blood flow, whereas urapidil enhanced blood flow significantly. Despite the increase in blood flow, the basal interstitial glycerol concentration remained unchanged. Although norfenefrine at high concentrations could inhibit the urapidil-induced increase in blood flow, the norfenefrine-induced glycerol output was not affected. These results demonstrate that alpha(1)-adrenoceptors are involved in regulation of lipolysis rate and microcirculation of adipose tissue. However, the observed changes in local blood flow were not related to glycerol output.


PMID 11907178

Full text to the second one - In Vivo


again, my question is on the effectiveness of each. Alpha-y is harder and more expensive to obtain compared to plain yohimbine hcl.

 

[JudoJosh]

structural diagrams of the compounds in questionYohimbine

Alpha Yohimbine

Possibly yohimbine is simply a racemic mix of the alpha and beta face stereoisomers?

 

[JudoJosh]

More on yohimbine

Yohimbine: the effects on body composition and exercise performance in soccer players.


The main aim of this study was to determine the effects of yohimbine supplementation on body composition and exercise performance in professional soccer players. The athletes (20 top-level male soccer players) were allocated to two randomly assigned trials. Subjects in the yohimbine group orally ingested tablets that contains yohimbine at a dose of 20 milligrams per day in two equal doses for 21 days. Subjects in the placebo group ingested an equal number of identical-looking pills that contained cellulose. There were no statistically significant changes in body mass and muscle mass within or between trials (p > 0.05) after the supplementation protocol. Percentage of body fat significantly decreased in the yohimbine group after the supplementation protocol (9.3 +/- 1.1 vs. 7.1 +/- 2.2%; p < 0.05). Furthermore, fat mass was significantly lower in the yohimbine versus placebo trial at postsupplementation assessment (7.1 +/- 2.2 vs. 9.2 +/- 1.9%; p < 0.05). There were no changes in exercise performance indicators (bench and leg press, vertical jump, dribble and power test results, shuttle run) within or between. trials (p > 0.05). No subject reported any side effects from yohimbine. The results of the current study indicate that supplementation with yohimbine combined with resistance training does not significantly alter the body mass, muscle mass, or performance indicators in professional soccer players. Nonetheless, yohimbine supplementation appears to be suitable as a fat loss strategy in elite athletes.


PMID:17214405

Pre-exercise administration of yohimbine may enhance the efficacy of exercise training as a fat loss strategy by boosting lipolysis.


The natural alpha-2 antagonist yohimbine promotes sympathetic activity by central as well as peripheral mechanisms, and yet in moderate doses dose not usually raise heart rate, increase blood pressure, or induce anxiety (in contrast to sympathomimetic drugs such as ephedrine). Administered prior to exercise, it boosts lipolysis and serum FFA levels both during and following exercise; blockade of adipocyte alpha-2 adrenoreceptors makes at least a modest contribution to this pro-lipolytic activity. These considerations suggest that pre-exercise administration of yohimbine will lower the respiratory quotient during and following exercise, thus promoting fat loss. Since yohimbine can potentiate postprandial insulin secretion, its bariatric benefits should be greatest if administered on a schedule that minimizes postprandial yohimbine activity. A possible synergism of yohimbine and caffeine should be explored. Pre-exercise yohimbine administration has the potential to down-regulate the lipoprotein lipase activity of visceral adipocytes, increase lipolysis in refractory gynoid fat depots, and improve the impaired lipolytic response to exercise in the elderly.


PMID:12323115

 

[rms80]

Which is more effective?


Alpha-y is touted as having less side effects but my question is, is it more effective?


My understanding is both alpha-y and y antagonize the alpha 2-adrenoceptors but y will also antagonize the alpha 1-adrenoceptors too which can hinder lipoysis and alpha-y will not (or at least not as much as y would.








Full text to the second one - In Vivo


again, my question is on the effectiveness of each. Alpha-y is harder and more expensive to obtain compared to plain yohimbine hcl.

From the SAR data I have seen, AY is the stronger of the two in terms of alpha 2 adrenergic binding; this may be the "buzz" about the effects of rauwloscine being "easier" to take than yohimbine. Both isomers are extremely potent, and even a small (0.5 mg) dose is enough to increase NE levels in the brain and SNS. I have a couple studies floating around here somewhere- we use a blend of the two isomers in Uncut, and keep the dose on the low side

On the analytical side, it gets sketchy- I had to go through 3 separate suppliers before we obtained real AY, the other supplier samples and specifications were actually for beta yohimbine, but with alpha transposed over on the CoA. You can take a look at our FT-NIR spectra for each compound in the Uncut write-up- there is one substantial difference in chemical bonding between the two.....what this tells me is that a lot of companies may think they are using AY, when they are really getting beta yohimbine, with the contract mfr/raw material supplier pocketing the difference ($700 kg vs $8,500, do the math)

 

[rms80]

Read the full text: "Effects of yohimbine, rauwolscine and corynanthine on contractions and calcium fluxes induced by depolarization and prostaglandin F2 alpha in rat aorta."

Rat study, but it gives some insight into binding potency and secondary characteristics (effects on HR and BP) amongst the 3....http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2044957/

Link to full text is posted

 

[mr.cooper69]

Well, the alpha-1-adrenoreceptor is a tough cookie. It's role in vascular constriction is fairly well understood; its role in lipolysis, not so much

 

[rms80]

Well, the alpha-1-adrenoreceptor is a tough cookie. It's role in vascular constriction is fairly well understood; its role in lipolysis, not so much

Especially since there is relative non-selectivity with a lot of compounds that show a strong affinity for a-1; many of them interact with 5-HT. BAR, A2, etc. Throw in polymorphisms on top of that, and it is a tough nut to crack, and because of the receptor having control over vasoconstriction, it might not be the safest area for human studies on lipolysis

 

[nidhogg]

Yohimbine is predominantly known as a selective alpha 2 antagonist. I think that the alpha 1 activity is blown out of proportion. If anyone has any reference on its IC50 value on alpha-1 then post it here.

Ofc, the word "selective" is used when a compound has significant receptor activity at a certain concentration while not influencing any other receptor to any significant degree. I have references that rauwolscine is also an alpha 1 antagonist just like yohimbine, in fact the study that was posted above is indicating that rauwolscine has a greater inhibitory effects on alpha-1 than yohimbine. Although the concentrations used are far above the serum concentrations of moderate usage.

Point being that if you "blast away" with any of these compounds you are going to tap into the inhibitory threshold of other receptors aswell.

The real problem with yohimbine is that it gets rapidly metabolized to two different hydroxylated compounds whose binding profile is fairly unknown, other that they also possess alpha-2 inhibitory properties. Most of the studies conducted are in vitro thus bypassing this problem.

 

[rms80]

Yohimbine is predominantly known as a selective alpha 2 antagonist. I think that the alpha 1 activity is blown out of proportion. If anyone has any reference on its IC50 value on alpha-1 then post it here.

Ofc, the word "selective" is used when a compound has significant receptor activity at a certain concentration while not influencing any other receptor to any significant degree. I have references that rauwolscine is also an alpha 1 antagonist just like yohimbine, in fact the study that was posted above is indicating that rauwolscine has a greater inhibitory effects on alpha-1 than yohimbine. Although the concentrations used are far above the serum concentrations of moderate usage.

Point being that if you "blast away" with any of these compounds you are going to tap into the inhibitory threshold of other receptors aswell.

The real problem with yohimbine is that it gets rapidly metabolized to two different hydroxylated compounds whose binding profile is fairly unknown, other that they also possess alpha-2 inhibitory properties. Most of the studies conducted are in vitro thus bypassing this problem.

Looked around a little bit- there are studies out the yang on IC50 for yohimbine and rauwloscine antagonism of a-2- I used "A2 Adrenoreceptors and Lipid Mobilization" by LaFontan et al for some of my yohimbine content- they looked at SAR for yohimbine and other alpha 2 antagonists (but not rauwloscine), and used a slightly different equation for Ki on page 223- they explain how they derived it at the bottom- some of the tables on that page are pretty interesting in terms of what structural characteristics determine increased affinity. I also used "A2-Adrenoreceptor antagonist potencies of two hydroxylate metabolites of yohimbine" by Berlan et al. (I think you were referencing this)- 11-OH-Yoh tends to present in plasma post-admin of yoh (10x the amount of yoh)- and 11-OH-yoh has a much longer half-life than yoh, but is much less lipid soluble (may have trouble crossing BBB); 10-OH-yoh doesn't really do much of anything at pharmalogical doses (p. 930-1) the antagonist potency to A2 is: yoh>11-OH yoh>10-OH yoh; to your point, in-vitro, however

You raise a good point, a "full-blast" dose of either of these compounds would actually be counter-productive, due to some of the other receptor sub-types than can potentially be effected- you want enough a-2 antagonism to increase NE in the brain and periphery, but not to the extent where many of the thresholds of other receptors are disturbed....

 

[nidhogg]

No one is doubting the inhibitory potency at the alpha 2 receptor, i was talking about IC50 values for the other receptors including alpha-1 of which there are none. Thus it is kind of hard to argue about which one is preferable over the other.

Although you raise a good point, the hydroxylated metabolites are more water soluble thus may have lower central activity than parent compound. Yohimbine is a fairly bulky alkane on the other hand with great lipophilic properties so a single additional polar functional group may not alter its permeability to any significant degree.

Nevertheless rauwolscine is indeed more lipophilic thus preferable, considering it can diffuse through the synapse and thus inhibit presynaptic alpha 2 receptors as well as having central activity. Since the NET does not bind to yohimbine, it relies heavily on being lipophilic.

Question still remains though, to what extent does one alcohol group alter the lipophilic properties of a large bulky carbon structure like yohimbine

 

[LiveToLift]

In for the good read.

 

[Geoforce]

Good read so far guys, very interesting stuff. I just can't take Yohimbine, hell reading about it makes me think back to how horrible I felt with my first experiences with that years ago. AY has always treated me good.

 

[rms80]

No one is doubting the inhibitory potency at the alpha 2 receptor, i was talking about IC50 values for the other receptors including alpha-1 of which there are none. Thus it is kind of hard to argue about which one is preferable over the other.

Although you raise a good point, the hydroxylated metabolites are more water soluble thus may have lower central activity than parent compound. Yohimbine is a fairly bulky alkane on the other hand with great lipophilic properties so a single additional polar functional group may not alter its permeability to any significant degree.

Nevertheless rauwolscine is indeed more lipophilic thus preferable, considering it can diffuse through the synapse and thus inhibit presynaptic alpha 2 receptors as well as having central activity. Since the NET does not bind to yohimbine, it relies heavily on being lipophilic.

Question still remains though, to what extent does one alcohol group alter the lipophilic properties of a large bulky carbon structure like yohimbine

Lambert et al. 1978 in "Pharmacological and biochemical properties of isomeric yohimbine alkaloids" stated that yohimbine activity wasn't dependant on lipid solubility, or the ability to access the CNS- but it was a rat study- and I don't entirely agree with the conclusion of the researchers. But if you take into consideration the activity of 11-OH yoh vs. 10-OH yoh, the difference in activity seems to have to do with the position of the hydroxyl and not necessarily just the presence of the hydroxyl itself. Berlan found that yoh bound to 5% albumin at a much higher capacity than 10-OH or 11-OH, so this could come into play as well as far as activity goes. Table 1 on page 930 looked at the inhibition constants, and found that the inhibition constant for yoh was altered significantly by the addition of albumin- 1.65 to 15.6 Ki (nM) for platelets; 2.74 to 25.3 Ki (nM) for adipocytes.

My speculation would be the greater the ring count, the less adding an additional hydroxyl would matter. On PEA-type or catecholamine molecules, with only one benzene ring, it would make all the difference in the world- I have in my notes the pharmacophore data for increasing or decreasing potency based on SAR; but on a bulkier structure with multiple rings, it may not cause as much of an alteration in lipid solubility. My guess would be that at this point the geometry of the molecule and relationship to bonding (puckered conformation v planar) and target receptor (binding pocket and angles) would become more and more important, as well as some of the other points mentioned above (again, only speculation)

 

[rms80]

Good read so far guys, very interesting stuff. I just can't take Yohimbine, hell reading about it makes me think back to how horrible I felt with my first experiences with that years ago. AY has always treated me good.

Geoforce- what was your dose? Most of the horror stories I have heard related to yoh have to do with higher dosages, or mixed yohimbe alkaloids; I would also be interested to know, based on what I have seen from testing multiple lots (personally on our hardware and through third party) of what was supposed to be AY from multiple suppliers, if it really was AY, and not BY, at a much lower dose than "normal". I deal quite a bit with raw material suppliers in both China and India (China moreso than India), and based on the information I have, I am not entirely convinced. The companies marketing products with this material have no way of knowing unless they test their own raws coming in to their facility, and then send them to their contract manufacturer. If they are sourcing their raws through their contract manufacturer, it is going to be really hard to do this.....but not impossible

These other companies may be doing this (I sincerely hope they are)- but based on some of the FDA inspection reports I have seen recently, I am not so sure......

 

[Geoforce]

Geoforce- what was your dose? Most of the horror stories I have heard related to yoh have to do with higher dosages, or mixed yohimbe alkaloids; I would also be interested to know, based on what I have seen from testing multiple lots (personally on our hardware and through third party) of what was supposed to be AY from multiple suppliers, if it really was AY, and not BY, at a much lower dose than "normal". I deal quite a bit with raw material suppliers in both China and India (China moreso than India), and based on the information I have, I am not entirely convinced. The companies marketing products with this material have no way of knowing unless they test their own raws coming in to their facility, and then send them to their contract manufacturer. If they are sourcing their raws through their contract manufacturer, it is going to be really hard to do this.....but not impossible

These other companies may be doing this (I sincerely hope they are)- but based on some of the FDA inspection reports I have seen recently, I am not so sure......

This was years ago I wouldn't have any idea. Avoided it religiously ever since. Honestly it has probably been close to 9 years since I took it. I don't even know if I would try it again at a lower dose, the experience was just that unpleasant.

 

[nidhogg]

Lambert et al. 1978 in "Pharmacological and biochemical properties of isomeric yohimbine alkaloids" stated that yohimbine activity wasn't dependant on lipid solubility, or the ability to access the CNS- but it was a rat study- and I don't entirely agree with the conclusion of the researchers. But if you take into consideration the activity of 11-OH yoh vs. 10-OH yoh, the difference in activity seems to have to do with the position of the hydroxyl and not necessarily just the presence of the hydroxyl itself. Berlan found that yoh bound to 5% albumin at a much higher capacity than 10-OH or 11-OH, so this could come into play as well as far as activity goes. Table 1 on page 930 looked at the inhibition constants, and found that the inhibition constant for yoh was altered significantly by the addition of albumin- 1.65 to 15.6 Ki (nM) for platelets; 2.74 to 25.3 Ki (nM) for adipocytes.

My speculation would be the greater the ring count, the less adding an additional hydroxyl would matter. On PEA-type or catecholamine molecules, with only one benzene ring, it would make all the difference in the world- I have in my notes the pharmacophore data for increasing or decreasing potency based on SAR; but on a bulkier structure with multiple rings, it may not cause as much of an alteration in lipid solubility. My guess would be that at this point the geometry of the molecule and relationship to bonding (puckered conformation v planar) and target receptor (binding pocket and angles) would become more and more important, as well as some of the other points mentioned above (again, only speculation)

You are correct about the position of the functional group determining the receptor activity, i wasn't stating otherwise. My point was that considering 11-ho-y having equipotent activity at the alpha 2 receptor as its parent compound and also considering the lack of information regarding its activity on other receptors, the main difference between rauwolscine and yohimbine(and metabolites) is the lipophilicity of said compounds.

Naturally, ofc, a single alcohol group to a large carbon structure like yohimbine does not do much like you stated. But keep in mind yohimbine already has has an alcohol, an ester and a secondary amine contributing to the polar movement of the molecule. While an additional alcohol group may not be enough to make yohimbine significantly water-soluble, it may be enough to decrease its permeability to membranes.

Personally i find yohimbine to be a very short acting stimulant, it may be general desensitization of the effects or it may be increased pre-synaptic alpha 2 activity as yohimbine continues being metabolized to its hydroxylated compounds. I am currently taking it for fat loss and for that purpose it does not matter anyway.

One thing i dont get though, why is rauwolscine called alpha-yohimbine when the carboxylic acid of rauwolscine is clearly on the beta position?

 

[rms80]

You are correct about the position of the functional group determining the receptor activity, i wasn't stating otherwise. My point was that considering 11-ho-y having equipotent activity at the alpha 2 receptor as its parent compound and also considering the lack of information regarding its activity on other receptors, the main difference between rauwolscine and yohimbine(and metabolites) is the lipophilicity of said compounds.

Naturally, ofc, a single alcohol group to a large carbon structure like yohimbine does not do much like you stated. But keep in mind yohimbine already has has an alcohol, an ester and a secondary amine contributing to the polar movement of the molecule. While an additional alcohol group may not be enough to make yohimbine significantly water-soluble, it may be enough to decrease its permeability to membranes.

Personally i find yohimbine to be a very short acting stimulant, it may be general desensitization of the effects or it may be increased pre-synaptic alpha 2 activity as yohimbine continues being metabolized to its hydroxylated compounds. I am currently taking it for fat loss and for that purpose it does not matter anyway.

One thing i dont get though, why is rauwolscine called alpha-yohimbine when the carboxylic acid of rauwolscine is clearly on the beta position?

lol- just caught that- think he got the structures mixed up- I will let him know

Gotcha on the first point- have "Binding of yohimbine stereoisomers to a-adrenoreceptors in rat liver and human platelets" on my desk by Ferry et al- it does look at a-1 as well. I have to get in the lab this afternoon to do a bunch of stuff- I will try to read through it if I get a second....doesn't tell the whole story, but it does have SAR activity for a-1 and a-2 on the different stereoisomers- I may be able to "read between the lines" a little bit if anything jumps out a me between structural relationship and binding potencies- I will post it up, especially if it has to do with changes in relation to lipid solubility- the data does kind of suck, and I think we are both looking in the right places

 

[mr.cooper69]

You are correct about the position of the functional group determining the receptor activity, i wasn't stating otherwise. My point was that considering 11-ho-y having equipotent activity at the alpha 2 receptor as its parent compound and also considering the lack of information regarding its activity on other receptors, the main difference between rauwolscine and yohimbine(and metabolites) is the lipophilicity of said compounds.

Naturally, ofc, a single alcohol group to a large carbon structure like yohimbine does not do much like you stated. But keep in mind yohimbine already has has an alcohol, an ester and a secondary amine contributing to the polar movement of the molecule. While an additional alcohol group may not be enough to make yohimbine significantly water-soluble, it may be enough to decrease its permeability to membranes.

Personally i find yohimbine to be a very short acting stimulant, it may be general desensitization of the effects or it may be increased pre-synaptic alpha 2 activity as yohimbine continues being metabolized to its hydroxylated compounds. I am currently taking it for fat loss and for that purpose it does not matter anyway.

One thing i dont get though, why is rauwolscine called alpha-yohimbine when the carboxylic acid of rauwolscine is clearly on the beta position?

It's been a while since I've taken chemistry, but isn't the alpha referring to the stereochemistry of the hydrogen on the 20 carbon (which is on the alpha position in rauwolscine but not in yohimbine)

 

[JudoJosh]

Does madchemist still post here?

Interested in his thoughts on this

Sent from my Samsung Galaxy S™II using Tapatalk 2

 

[nidhogg]

It's been a while since I've taken chemistry, but isn't the alpha referring to the stereochemistry of the hydrogen on the 20 carbon (which is on the alpha position in rauwolscine but not in yohimbine)

Lol yea you are right, that is probably what they are referring to. The optical rotation of the ester sticks out much more in the image and draws all focus. Didnt even notice the hydrogen.

 

[RecompMan]

Maybe it's called alpha y because its top dog in its category as far as extracts?

 

[Raw Dog]

Maybe it's called alpha y because its top dog in its category as far as extracts?

I always said the same, then I tried enhanced. AY is still pretty damn awesome though