Original Post by Psychomanthis aka Iudicium Infernalum with a post by Gun Lover and myself afterwards.
We're all aware of normal modes of potentiation which mostly involve slowing down the metabolism of the drug we're trying to potentiate. However the purpose of this thread is to explore potentiation via allosteric modulation.
Now you might ask; what is allosteric modulation? It's quite simple really. Most receptors have multiple sites where substances can bind. Two of these sites are called the regulatory site and the active site. The active site is where the endogenous ligand binds and a receptor can have more than one of these. Now the regulatory site is where an allosteric modulator can bind to increase or decrease the binding affinity of the receptor. A molecule that can bind to this regulatory site is called an allosteric modulator. When you have a positive allosteric modulator binding to the regulatory site, the binding affinity of that receptor is increased and when you have a negative allosteric modulator binding to this site the binding affinity is decreased.
An excellent example of this lies with diazepam's mechanism of action and the GABAA receptor subtype. Diazepam functions as a positive allosteric modulator by binding to the regulatory site at the GABAA receptor thereby increasing the binding affinity of GABA which contributes greatly to it's overall pharmacological profile.
As all G-protein coupled receptors have a regulatory site it is simply a matter of finding the right allosteric modulator to potentiate anything from opiates to amphetamines.
I hope you enjoyed my brief introduction to allosteric modulation and it's implications as far as potentiation goes. If you have anything to add please feel free to post it! Also, if you have found flaws in my explanation please feel free to post them aswell. My intent with this thread was to start a discussion on the possibilities of potentiation via allosteric modulation and to come to a better understanding, together, as a whole, of the complexities of the subject at hand.
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Abstract
"The mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of saturation binding experiments. The aim of the present study was to examine whether cannabidiol is an allosteric modulator at this receptor, using kinetic binding studies, which are particularly sensitive for the measurement of allosteric interactions at G protein-coupled receptors. In addition, we studied whether such a mechanism also extends to the delta opioid receptor. For comparison, (-)-Δ9-tetrahydrocannabinol (THC; another major constituent of cannabis) and rimonabant (a cannabinoid CB1 receptor antagonist) were studied. In mu opioid receptor binding studies on rat cerebral cortex membrane homogenates, the agonist 3H-DAMGO bound to a homogeneous class of binding sites with a KD of 0.68±0.02 nM and a Bmax of 203±7 fmol/mg protein. The dissociation of 3H-DAMGO induced by naloxone 10 μM (half life time of 7±1 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 12 and 2, respectively. The respective pEC50 values for a half-maximum elevation of the dissociation rate constant koff were 4.38 and 4.67; 3H-DAMGO dissociation was not affected by rimonabant 10 μM. In delta opioid receptor binding studies on rat cerebral cortex membrane homogenates, the antagonist 3H-naltrindole bound to a homogeneous class of binding sites with a KD of 0.24±0.02 nM and a Bmax of 352±22 fmol/mg protein. The dissociation of 3H-naltrindole induced by naltrindole 10 μM (half life time of 119±3 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 2, each. The respective pEC50 values were 4.10 and 5.00; 3H-naltrindole dissociation was not affected by rimonabant 10 μM. The present study shows that cannabidiol is an allosteric modulator at mu and delta opioid receptors. This property is shared by THC but not by rimonabant."
Just as cannabidiol in this example is used as a negative allosteric modulator for the mu-opiate receptor, we should focus on a positive allosteric modulator to increase the effects of a mu-receptor agonist we co-ingest.
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Found a 5-HT2 allosteric site study. There's a ton of 5-HT3 studies.
http://www.ncbi.nlm.nih.gov/pubmed/2444794Abstract
Vascular conductance in the mesenteric, hindquarter, and renal beds of the conscious rabbit was derived from regional blood flow (pulsed Doppler flowmeter) and ear artery pressure. After autonomic ganglion blockade (mecamylamine), serotonin (5-HT, 5-hydroxytryptamine) infusion, 3-60 micrograms/kg/min i.v., dilated the mesenteric and hindquarter beds but caused renal blood flow to fall to zero. Angiography confirmed that serotonin had caused the conduit renal arteries to spasm. This response was unaltered by 1 mg/kg prazosin but was antagonised by 0.5 mg/kg ketanserin and 0.5 mg/kg methysergide. Only the latter drug shifted the dilator-response curves in the other two beds. Methiothepin, 1 mg/kg, flattened both the dilator and constrictor response curves, perhaps by binding to an allosteric site on the serotonin receptor. 5-Carboxamidotryptamine (5-CT) caused about half the renal arteries to spasm at less than 30 ng/kg/min and dilated the other beds. From the antagonist data, we suggest that 5-HT2 receptors mediate the contraction of the renal artery, but that "5-HT1-like" receptors mediate the dilatation in the renal, mesenteric, and hindquarter beds in the conscious rabbit. 5-CT is not helpful in defining the receptors in the renal artery. The rather special spasmogenic response to serotonin in the renal artery is worthy of further research to reveal what factors may lead to large artery spasm.
Got another type 2 modulator, but it also effects type 7.
http://www.pnas.org/content/94/25/14115.full.pdf"Previous studies demonstrated that oleamide potentiated
5HT2Ay2C-mediated chloride currents in the frog oocyte
expression system (4), so we investigated whether oleamide
could modulate this receptor subtype in rat P11 cells, which
endogenously express the 5HT2A subtype coupled to phosphoinositide
hydrolysis (6). In these cells, 5HT caused a concentration-
dependent increase in inositol phosphate formation
with an EC50 of 10 mM (Fig. 1B). In the presence of an EC50
concentration of 5HT, oleamide caused a concentrationdependent
increase in inositol phosphate turnover, resulting in
a substantial potentiation of the 5HT response (Fig. 1A). At a
concentration of 100 nM, oleamide caused a significant potentiation
of the 5HT concentration–response curve, resulting
in an increase in the maximal 5HT response by 228% (Fig. 1B).
Oleamide, by itself, had no significant effect of inositol phosphate
formation in these cells (data not shown)."
Found the perfect publication for your serotonergic consideration.
http://molpharm.aspetjournals.org/co.../1/78.full.pdf"To search for positive allosteric modulators, the Pharmacia
chemical library was screened with use of the assay of [3H]5-
HT binding to the human 5-HT2C receptor. The receptor was
heterologously expressed in HEK293 cells at a density of
45 3 pmol/mg of protein (HEK293-A). From the screening,
we discovered PNU-69176E (Fig. 1), which at 10 M markedly
stimulated [3H]5-HT (2 nM) binding (300%). The concentration-
response profile for PNU-69176E was biphasic
(Fig. 2A). At concentrations of less than 25 M, the drug
enhanced [3H]5-HT binding, but at higher concentrations it
decreased binding. Peak stimulation of [3H]5-HT binding by
PNU-69176E was observed at the drug concentration of 25
M, with a net increase of 355 37%, as normalized to that
in the absence of the drug. As the drug concentration increased
to levels greater than 25 M, [3H]5-HT binding decreased
gradually and disappeared at the drug concentration
of 200 M. The latter phase is probably caused by disturbances
of membrane structures by the amphipathic PNU-
69176E, which contains both a hydrophobic long alkyl chain
and a polar head group (Fig. 1). The biphasic profiles fitted to
a two-site logistic equation. The stimulatory phase for PNU-
69176E showed an EC50 value of 6.3 1 M and a slope of
2.3 0.5, and the inhibitory phase showed an IC50 value of
61 5 M and a slope of 3.6 0.6 (Table 1; Fig. 2A). Also,
saturation binding assays for [3H]5-HT at concentrations
from 0.09 to 48 nM were carried out with or without PNU-
69176E at 10 M (Fig. 2B). Without the drug, [3H]5-HT
binding linearly increased and showed no sign of saturation,
even at 48 nM [3H]5-HT. In contrast, in the presence of
PNU-69176E (10 M), 5-HT binding data fitted to one sitebinding
model with a KD of 17 0.8 nM and maximal binding
of 32 0.8 pmol/mg of protein, which accounts for nearly 80%
of the total binding site, as estimated from [3H]mesulergine
binding."
Now to look for dopamine and opioid receptors.
The only thing I could find for opiates is THC and Salvinorin A which is a negative modulator, AND we all know how fun salvinorin A is.
One for dopamine.
http://www.ncbi.nlm.nih.gov/pubmed/19271750Abstract
"Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor."
It seems to me, in my short time researching, that there aren't too many allosteric modulators of the "good" receptors yet, and the ones that do exist, aren't quite specific enough for our needs. I'll continue searching, but I think I've found most of what I'm going to. Allosteric modulation still seems to be a new target in its own, yet alone in it's ability to enhance recreational drugs.
