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Potency and a Methyl group

Ham-milton

Ham-milton

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Jul 20, 2007
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I was trying to figure out today if this methylated methaqualone derivative 3-(2,4-dimethylphenyl)-2-methyl-quinazolin-4-one is going to be more potent than the parent drug.

140px-Methylmethaqualone.png


Is there a way to predict when and where a methyl group needs to be to increase the potency of a drug, or does it always increase potency (barring something like 3-methylmorphine, where the addition completely inactivates it)?

Obviously, lipophilicity is the major reasons the addition makes a drug more potent; I assume that this is something that can be predicted quite well?

Does it matter where the methyl group is located?
 
well for one, like i said in the other thread alkyl groups are electron donating, along with amino groups with a lone pair. yes, it matters where the methyl group is located because in the presence of more symmetrical polar bonds they help cancel out eachother - decreases polarity. since the alkyl and amino group are both electron donaters i would imagine another methyl group attached to the phenyl ring (in the position it's at) would make the polar bonds more 'symmetrical'...

edit: read up on electron density and you will begin to understand whats going on with the electron cloud and polarity. i still would like some more chemists here to jump in and let me know if im missing anything because i love orgo and id love to learn more...
 
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It would, if there was an electronegativity difference between the atoms involved... but seeing as this is C - C it shouldn't matter?
 
a C - C bond basically has no inductive effect going on right? so in essence, lets say, ethane is a non-polar bond... so any C to C bonds aren't going to affect polarity? i wonder if there is more than electronegativity between the atoms that would affect this question. as in a question i asked elsewhere, would toluene and m-xylene be equal in polarity or are any non-polar bonds added not going to affect the net charge?
 
Methyl substitution on a aromaticised ring (like a benzene ring) changes polarity because it affects the delocalisation of the electrons, and so the electron density in certain regions. This is why substitution on a ring produces directing effects on further substitution to the ring.
All this said I don't think it will change it all that much.
Benzene has a dielectric constant of 2.3, but methylbenzene (toluene) has a dielectric constant of only 0.1 more, 2.4. As you can see, not much of a change at all!
Well, this is AFAIK. I don't have that good a handle on this area...
 
^ like said above the potency prolly is increased moreso because of the methyl added to a slightly more electronegative atom - that being N. the question is how different would the potency be if another C - C bond were to be added... hmmm my head hurts. and i need a shower haha
 
The active dose is the same, according to SAR studies. The 2,4 dimethyl compound has been reported in Germany.
 
I could be wrong, but I'm fairly sure I remember right.... I'm not sure about actual potency, but in terms of oral Bio-availability, taken orally more would be able to be absorbed than if it was unmethylated right?

The only points I can think of to compare what I mean is injectable testosterone....Normally, it would be a waste to take orally,thus why it is injected. However, when a methyl group was added making M1T or Methyl-Testosterone it became dramatically more easily absorbed orally.But it also can potentially cause more liver damage because of this.
 
Unfortunately testosterone is way too different to apply rules here, though.
 
I'll upload a methaqualone SAR on blacklight if you want to check there, it will be in the depressants forum. The only drawback is that it is in German, but the numbers in the tables are still readible.
 
thanks, I shouldn't have too much problem with it; 5 years of language courses.
 
I just find learning German to be one of the most useless things to do. People could say the same about chemistry since its impact on everyday situations is virtually nil. I dont see myself visiting Germany anytime soon even though its not THAT far to travel from the UK. That's the best way to pick up the language though, watching German adverts on TV etc, it rubs off effortlessly. I cant bear the introdutory courses though, they are way to oversimplified and repetitive.
 
Smyth said:
I just find learning German to be one of the most useless things to do. People could say the same about chemistry since its impact on everyday situations is virtually nil. I dont see myself visiting Germany anytime soon even though its not THAT far to travel from the UK. That's the best way to pick up the language though, watching German adverts on TV etc, it rubs off effortlessly. I cant bear the introdutory courses though, they are way to oversimplified and repetitive.
Click to expand...

^ I guess that is certainly true if you want to know how to say in German, " discount sale special value hurry down to get a discount {insert consumer item} while stocks last..."
:)
I have found that over the years Chemische Berichte and the other German language journals are gold mine of information.
 
War yeah, a few years ago i embarked on reading the german methadone articles rhodium had retrieved *not* because i had any propitious hope of ever doing anything with methadone, rather I relished the opportunity for learning the Deutsche Sprache.

Haha, things have changed. Ive used quite alot of language media since then and while my working knowledge does not flow as smoothly as a well oiled bicycle chain, ive sorta run outta steam here.

Put simply, im interested in encountering real-life situations where it is useful to know information, i.e. the applications and *not* just dumbed-down timeless principles. Undoubtedly, this is important for being an academically more rounded person but in "the real-world" people wont care if u spelt Grignard reagent "Girnard" etc.

Anything you need to know chemicalwise is written/translated into the English language. Only very rarely will u need to speak foreign languages to access some information. The one exception to this was an esp@ce patent on ohmefentanyl written in Chinese!

CrOOk told me something about needing to speak Portugese to communicate with Brazilian Mimosa Hostilis farmers but this is not really my idea of tea & cake.
 
In this case, i think, electron density, polarity or lipophilicy don’t rule!
These features are much better affected by halogens, OR or NR substituents.
More often a methyl group fills out an additional space in the binding cavity and leads so to a better binding or higher affinity. Compare this to the glove-model of protein-ligand binding. If one has only 3 or 4 fingers, he could also wear a 5-finger glove, but it won’t fit perfectly. But if one would have 6 fingers, there would probably occur also some problems for the fit. I really like this model very much. It also explains better binding of the right enantiomer: You can wear a right hand glove at the left hand, but you will require more effort and energy.

In some other cases, a methyl group acts as a conformer anchor which hampers free rotation around a single bond and leads so to a more favoured conformation.

A methyl attached to O, S or N has an other effect: OH, SH or NH can act in the binding cavity as H-bond donors (due to the loosely bound acidic H) but also can act as a H-bond acceptor (due to the lonepairs). OMe, SMe and NMe or NMe2 only act as acceptors.
But here lipophilicy might also be crucial!

Last, but surely not least, a methyl group can affect the drug degradation in the body.

-Have a nice weekend!!
 
Ham-milton said:
Is there a way to predict when and where a methyl group needs to be to increase the potency of a drug, or does it always increase potency (barring something like 3-methylmorphine, where the addition completely inactivates it)?

Obviously, lipophilicity is the major reasons the addition makes a drug more potent; I assume that this is something that can be predicted quite well?

Does it matter where the methyl group is located?
Click to expand...

Ok, back to the original post.

EN21 already said a good deal. Especially the "glove-model" helps here a lot. For a precise prediction of the different binding modes with an additional methyl present/missing you need a structure of your target. This is normally some kind of receptor or another protein. To my knowledge, there is no definite target for methaqualon known, especially not with structure. So, this is pure theory in this case...

For sure, one cannot say, that a methyl group always increases potency. The example of 3-Me-morphine is already very helpful and shouldn't be considered as sheer exception. An additional methyl does increase lipophilicity but that doesn't go along straight with potency. Just an example: Higher lipophilicity decreases oral bioavailability to some degree.

May you think about that one:
For peroral bioavailability Lipinski et al stated in 1997 what was later called "The Rule of 5". A "good" drug in this sense is present, when you have:
- molar weight below 500
- less than 5 hydrogen-bond donors (expressed as the sum of OHs & NHs)
- less then 10 hydrogen-bond acceptors (expressed as the sum of Os & Ns)
- clogP < 5
- and when the molecule is not substrate of an active efflux transport.

Lipophilicity can be predicted quite well (clogP) as it can be measured (logP) but higher lipophilicity does not mean automatically higher potency!!!

Murphy
 
immaturepoop said:
well for one, like i said in the other thread alkyl groups are electron donating, along with amino groups with a lone pair.
Click to expand...
That is not really correct. Yes, a methyl substituent got a +I-effect on the aromatic ring, but an amino group shows an -I-effect! That's the first difference.
While methyl exhibits no M-effects at all, an aniline does provide a +M-effect. Because that one weights more, the amino group exhibits in summary an electron-donating effect, as does methyl. But they for sure don't go "along", as 1. the similarity is just for pure coincidence (e.g. Ar-OH and Ar-NH2 have much more in common) and 2. the effects are nor comparable (+I by methyl is very weak, +M by NH2 is quite significant).

immaturepoop said:
yes, it matters where the methyl group is located because in the presence of more symmetrical polar bonds they help cancel out eachother - decreases polarity.
Click to expand...
Methyl always decreases polarity.

Murphy
 
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