China White + Angel Dust = Chemical Hybrid Heaven?

[PrimoPyro]

I know I can't be the onle bee here to have ever wondered what a very special hybrid drug analog might be like. There are all kinds of drugs that could be altered to be weird hybrids of two drugs, or even more.

One such hybrid I've been thinking about, is between PCP, a dissociative, and Fentanyl, an incredibly powerful opioid. First, let's take a look at the PCP molecule.



It is not a phenethylamine, it is a benzylamine. It's alkyl chain is one shorter than a phenethylamine. Amphetamines are still phenethylamines, with a methyl on the beta carbon. This phenyl-cyclohexylamine is a benzylamine, as the amine is attached to the benzyl carbon.

Fentanyl looks like this:



Fentanyl is a phenethylamine. Notice any similarities between PCP an Fentanyl? They both have the amine grafted as part of a piperidine ring. PCP has no additives to the ring, while Fentanyl does. A hyvrid structure of the two would look like this:



This would be a variant analog of both drugs. For a PCP analog, it contains an anilino/propionamide at the 4-piperidine position.

For a fentanyl analog, the alkyl chain is shortened one for the phenethylamine, and the benzyl carbon holds together a five carbon chain, forming a cyclohexyl group.

I seriously think this compound may be a real goody, and wonder if it has ever been synthesized. I have thought about it's synthesis, and so far I find that you can take any number of really impractical synthesis pathways, or you can just build the piperidone ring around phenylcyclohexylamine, as if it were phenethylamine.

Perhaps a synthesis might look like:

1.Phenyl-Cyclohexane --> Phenyl-Cyclohexylamine,

Post 281087 (missing)

(PrimoPyro: "PCP Analog Precursors From Phenyl-Cyclohexane", Chemistry Discourse)  
2.Phenyl-Cyclohexylamine --> (di)methyl acrylate diester (is this the Michael Addition?)
3.Diester is decarboxylated to give 1-(Phenyl-Cyclohexyl)-piperid-4-one.
4.Normal Fentanyl synthesis from here. Condense with aniline and reduce, and react with propionic anhydride.

                                                    PrimoPyro
Vivent Longtemps La Ruche!

[slappy]

This drug wouldn't be active. N-Benzyl Fentanyl analouges are almost completely inactive. Fentanyl gains it's extreme potency be cause the N-phenethyl group snakes it's way deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains of the µ-Opioid Receptor. Even if you did add another carbon, the cyclohexane would provide too much steric crowding too be able to bind properly. It probably wouldn't be active at the sigma-receptor or PCP receptor sites either, because they ususally favor smaller inactive (=not heteroatomic) substituents.

You can't just cut and paste molecules together and expect them to exibit activity at both sites. That's why you make two drugs, and take them at the same time .

Molecular Docking Reveals a Novel Binding Site Model for Fentanyl at the µ-Opioid Receptor.
Journal of Medicinal Chemistry, 2000 43(3) 381-391

[Fully_Auto]

Fully_Atuo likes your molecule. If you get it made Fully_Auto will eat it and go on a naked rampage terrorizing the town.
The Ultimate Weapon Can't be controlled, banned or confiscated. Your weapon's your mind.

[PoohBear4Ever]

Didn't you read the reply? It's more than likely not active!

PB

[PrimoPyro]

You can't just cut and paste molecules together and expect them to exibit activity at both sites. That's why you make two drugs, and take them at the same time

I am aware of this. I only explained it in this manner because I wanted some replies. When I fail to make analogies in my posts, apparantly people don't know what to say (perhaps they cannot identify?) and my threads die into the dust. So I had a genuine idea merely regarding the cyclohexylamine substitute, and decided to show that it was similar to PCP to illustrate why it might have drug action.

Slappy, thank you for your post. You have opened up a can of worms for yourself now. Prepare for the barrage of questions in my next PM.  

And thank you for the reference, I think I will be able to locate that at my library. I really appreciate this.

                                                   PrimoPyro

Vivent Longtemps La Ruche!

[Fully_Auto]

I can read. Fully_Auto will still eat it active or inactive and go on a naked rampage.

[PoohBear4Ever]

"Go to Jail. Go directly to jail. Do not pass go. Do not collect $200."

PB

[Fully_Auto]

The Ultimate Weapon Can't be controlled, banned or confiscated. Your weapon's your mind.

[Cyrax]

Damned, I can't get my hands on that Journal of Medicinal Chemistry article.  If somebody could send it to me in .PDF format, I would be gratefulll   .

Slappy, you said:
Fentanyl gains it's extreme potency because the N-phenethyl group snakes it's way deep in a crevice between transmembrane helices II and III

It seems that an alpha methyl on the phenethyl group seems to give good ligand - receptor interaction:
 * fentanyl = 100 x morphine & alpha-methyl-fentanyl = 200 x morphine.
 * acetyl-fentanyl = 1 / 14 x fentanyl & acetyl-alpha-methyl fentanyl = 10 x morphine.
I also have heard that the alpha methyl makes the effect long lasting.  Is this right?  How long is long lasting?

Now, I have been wondering: what is the effect of a beta hydroxy group like in beta-hydroxy-fentanyl?  I have been searching for info about this compound, but I found zip   .  How strong is it, compared to fentanyl?

[tiresias3]

slappy,

What if you replaced the benzene ring of fentanyl with a 3,4-methylenedioxybenzene ring instead?

[Rhodium]

Molecular Docking Reveals a Novel Binding Site Model for Fentanyl at the µ-Opioid Receptor
Subramanian, G.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M.

J. Med. Chem. 43(3), 381-391 (2000) 

(https://www.thevespiary.org/rhodium/Rhodium/pdf/fentanyldocking.pdf)
DOI:

10.1021/jm9903702

Abstract

The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the mu-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable "bioactive" structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chimeric and mutant receptor studies as well as structure-activity relationship data reported on a wide range of fentanyl analogues. The binding site model is also compared to that of N-phenethylnormorphine. An overlay of the bound conformation of the opiate and cis-3-methylfentanyl shows the N-phenethyl groups occupy equivalent binding domains in the receptor. While the cationic amines of both ligand classes were found docked to an established anchor site (D149 in TM-III), no overlap was observed between the N-phenylpropanamide group and the remaining components of the opiate scaffold. The unique binding mode(s) proposed for the fentanyl series may, in part, explain the difficulties encountered in defining models of recognition at the mu-receptor and suggest opioid receptors may display multiple binding epitopes. Furthermore, the results provide new insight to the design of experiments aimed at understanding the structural basis to the differential selectivities of ligands at the mu-, sigma-, and kappa-opioid receptors.

[Dr_Heckyll]

4-(2-Fluoro-phenyl)-1-(1-phenyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridine

Developed by Grünenthal (those who developed tramadol) as a ligand for the PCP and µ-opioid receptor. It binds to both receptors with approximately the same affinity, therefore is, at an active dose, both an NMDA antagonist and a µ-agonist. Ref:

Patent WO0220481

Dr. Heckyll & Mr. Jive by Men at Work
...tells my tale.

[Dr_Heckyll]

slappy: N-Benzyl Fentanyl analouges are almost completely inactive.

Interestingly, though, some N-Benzyl derivatives of Pimozide and Benzperidol-type neuroleptics are potent but short-acting opioids. Just don't ask for refs, I really don't feel like diggin' for that stuff   .


Dr. Heckyll & Mr. Jive by Men at Work
...tells my tale.

[Cyrax]

Whow, that is a nice patent.  Thx for bringing that to my attention.

[Cyrax]

TITLE Enantiomeric N-Substituted N-Normetazocines: A Comparative Study of Affinities at ?, PCP, and ? Opioid Receptors
AUTHORS Carroll, F. I.; Abraham, P.; Parham, K.; Bai, X.; Zhang, X.; et al.
SOURCE J.Med.Chem. 1992, 35: 15 2812-2818
DOCUMENT TYPE Journal
CODEN JMCMAR
LANGUAGE EN
CNR 5657570
ABSTRACT The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the ? receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors.Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine <(+)-4, (+)-pentazocine> was more potent and selective for the ? receptor.In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their ?-1 ((3H)-(+)-3-PPP or (3H)-(+)-pentazocine), PCP ((3H)TCP), and ? opioid ((3H)DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine ((+)-10) possessed subnanomolar affinities for the ? site, Ki = 0.67.The analog (+)-10 showed >14000- and 2400-fold selectivity, respectively, for the ? receptor relative to the PCP and ? opioid receptors.The N-substituted N-normetazocines were enantioselective for the ? site.The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10.Analysis of the data also revealed that (+)-normetazocine ((+)-1) possessed the highest affinity for the PCP receptor.However, (+)-metazocine ((+)-5) (Ki = 41 nM> was the most selective compound for the PCP receptor relative to the ? (51-fold) and ? opioid (> 200-fold) sites.
COPYRIGHT Copyright © 1988-2001, Beilstein Institut für Literatur der Organischen Chemie licenced to Beilstein Chemiedaten und Software GmbH and Beilstein Informationssysteme GmbH. All rights reserved.

[Cyrax]

What if you replaced the benzene ring of fentanyl with a 3,4-methylenedioxybenzene ring instead?

Tireias3, it is a bad idea to substitute 3,4-methylenedioxyaniline for aniline in the fentanyl synthesis.  Fentanyls with a substituent on the 4 position are less potent, and this is even more the case if the group is on the 3 position: then the analog will be far less potent.

I can illustrate this with the ED50s (mg / kg) of a few fentanyl analogs:
* 1-(2-phenylethyl)-4-(N-PHENYLmethoxyacetamido)piperidine 0.08
   ...4-(N-(4-CHLOROPHENYL)...                        0.5
   ...4-(N-(3-CHLOROPHENYL)...                        2.1
   ...4-(N-(3-CHLORO-4-METHOXYPHENYL)...              2.8

 * 1-(2-(2-thienyl)ethyl)-4-(N-PHENYLmethoxyacetamido)piperidine 0.004
    ....4-(N-(3,4-METHYLENEDIOXYPHENYL)....              0.3

  Organic nomenclature, isn't it wonderfull  

[PrimoPyro]

that he meant replace the ethylbenzene with 3,4-MDP-Et- group, not the aniline.  

[tiresias3]

Thank you, PrimoPyro.

[PrimoPyro]

In which case, the answer to your question can be found by reading this thread from its beginning, and locating the short lecture I recieved from slappy on combining molecular structures hoping for mixed effects. It doesnt work that way.

Its a really interesting discussion. You should read it. You kind of have to lure slappy out, he doesnt talk much or often, but when you get him to, you'll always learn a lot.

[tiresias3]

If an alpha methyl group is added to the Ph-Et-amino chain, you get alpha-methylfentanyl which is more potent than fentanyl.  So slappy would be wrong in that case.  My question is has the compound to which I referred been tested for pharmacological activity yet?  And even if you had been right, PrimoPyro, a minimally effective dosage of your PCP would be a lethal dosage of your fentanyl.