Molecular similarity necessarily entails similarity in effect - NOT!

I find that one of the most confusing and therefore problematic things about the perception of psychoactive substances is that most people are convinced that molecular similarity necessarily entails similarity in effect. I have mentioned a few times that in practice this is not the case (the QSAR paradox). But since this is an important point that people are often confused about - I will also dedicate this post to it. I examine the point of using 3 different cathinone analogues that I have developed. Prima facie, they are similar. They actually have the same molecular weight and a mass-spectography will show identity in mass. The difference between them is the location of the methyl group on the benzene ring - and this difference can have significant ramifications.

So we have and know 4-MMC, 3-MMC and 2-MMC.

What is the difference between them?

4-mmc mephedrone

3-mmc metaphedrone

2-mmc orthophedrone?

Three molecules are shown in the comments and I think it's not hard to convince that they are different from one another but generally quite similar to each other. Right?

Well yes, so long as we look at them as represented on a two-dimensional schema, or a sheet of paper, if you will…

But if you are to represent these three molecules as they appear in three dimensions to the world in which they live (the world in-between-synapses surrounded by brain fluid) what you would see is three objects which have spatial and electromagnetic differences that are different enough to dramatically skew their trajectories (mostly driven by brownian and motion) so that 4-MMC will bind to certain receptors 3-MMC to others and 2-MMC to others yet again.

The way that molecules bind to receptors is a probabilistic magic that is difficult to describe. But I'll rise to the challenge because I believe it worthwhile and rewarding to share with others what it is that I see in my mind's eye.

The course of a molecule until it “docks” in a receptor is sometimes described in mathematics as a ‘drunken walk’. It is a jitter and a jigger and a kind of a dance that surprisingly but almost inevitably leads our dancing molecule to the same receptor more often than not again and again. Statistically it is a majority but in practical terms it is a certainty.

Now this difference in trajectory which causes a difference in affinity ends up making the three molecules act as if they are a pianist playing three different chords.

4-MMC, as it happens has an affinity to 5-ht2b receptors which are also present on the heart. A chemical agent floating around in your bloodstream with the capability to bind to 5-ht2b receptors on the heart and thereby change the rhythm of your heartbeat makes you feel like you're in love if you are young and healthy and attending a dance rave - and many people that have tried mephedrone in this setting found this feeling to augment their general enjoyment of their jovial and pirouettic predicament. But in another setting this same tachycardia is very unpleasant. If the body was a country, then these molecules floating around would be equivalent to giving lunatics loaded beebee guns. Quite a mess to clean up after these madmen shot their loads at who and where…

3-MMC effects the heartbeat in a much milder and much more predictable way, and it isn't clear to me if this is effected by way of interaction with receptors on the heart at all. My opinion is, that it is a general rule, that if one is to compare the pharmacokinetics of 3-MMC to that of MDMA or mephedrone - then 3-MMC’s profile is much more predictable and resultantly - more “boring”. But this can also be described as an effect that is more cognizant and less “lovey-dovey”...if you will. What I find fascinating here is that the origin of these differences can be found directly in the geometry of the space filling form of the molecule and the geometry of the probability cloud of the molecule’s charge distribution.

2-MMC is, again, another story. A story that, I am sad to say, I must cut short into a brutal summary which goes along the lines of “I found it to be very different from 3-MMC”. The reason for this is that I did not explore this compound extensively because for me, a few experiments that told me repeatedly that it was unlike 3-MMC - was all that I needed in order to “wrap up” my inquiry with that molecule and go back to testing, exploring and enjoying 3-MMC.