04-19-00 05:51
No 122775
      heterocyclic amphetamine analogs -Beagle
(Rated as: excellent)

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Author  Topic:   heterocyclic amphetamine analogs 
Member   posted 12-03-98 06:39 PM          
Has anyone ever looked into amphetamine or PEA analogs where another aromatic ring replaces the phenyl? This is such an obvious thing to do that there is no question that it has been done by various pharmaceutical co.s, but has it been published? I am aware of alpha-methyl tryptamines and sidechain constrained analogs like aminotetralins and aminoindanes, but what about the thiophene, furan, pyrrole, pyridine, etc analogs? Anyone?
Someone I never met once told me that they had some 2-thienyl lithium sitting around that they wanted to put to good use. Any suggestions for best route from this?

drone 342
Member   posted 12-03-98 11:13 PM          
Oh yes, yes, yes! I've been talking about it for a while, and I've been hoping someone would want to discuss this. There have been 2-napthalene isopropylamines, benzofurans, thianapthalenes, pyridines, and everything you can think of. The benzofuran and thianapthalene ones look the most fascinating to me. Which ones would you like info on?
-drone #342

Member   posted 12-04-98 01:49 AM          
Thianaphthene and benzofuran definately sound interesting. The nice part about these cpds is that rotating the point of attachment of the alkyl chain around the ring gives some interesting points to compare. When the chain is at the 3 position you have a tryptamine analog, when you move it over to the 5 or 6 position you have more of a MDA analog.
But all of the compounds you mentioned interest me. Do you know any particulars?

Member   posted 12-05-98 09:36 AM          
When I was checking to see what kinds of precursors for these cpds are commercially avial., I came across this item at Aldrich #357839: 1,5,6,7-Tetrahydro-4H-indol-4-one 98% 5g/31$. Cool, huh. Thats got to be the cheapest, easiest precursor to psilocin and other 4-OH indoles I've ever seen. Aromatization would be simple. I've always wondered about 4-OH-MIPT...

Member   posted 12-05-98 09:38 AM          
When I was checking to see what kinds of precursors for these cpds are commercially avial., I came across this item at Aldrich #357839: 1,5,6,7-Tetrahydro-4H-indol-4-one 98% 5g/31$. Cool, huh. Thats got to be the cheapest, easiest precursor to psilocin and other 4-OH indoles I've ever seen. Aromatization would be simple. I've always wondered about 4-OH-MIPT...

Member   posted 12-05-98 12:54 PM          
Welcome to the tryptamine fan club, beagle. If you are interested in discussing the OH-indole synthesis, please start a new topic (for short: your substance is cheap at Aldrich, but it's much cheaper and very easy to synthetize on your own. I heard of someone doing it. See Het. 22, 2313 1984).
Back to non-tryptaminic heterocyclic analogues: I had these dreams some years ago. Let's look into my old files:

(1) Here two scientists write about their heroic self experiments: "...and there can be no doubt that the 2-thienyl- and 2-furyl isopropylamines are relatively ineffective central nervous system stimulant...". What a pity!
(2) gives the synth of 5-substituted 2-thienyl isopropylamines from aldehydes: H, Br, I.
(3) gives the synth of 2-thienyl isopropylamine from aldehyde.
(4) Gives cool data and synth. of 3/4/5-Cl-substituted 2-thienyl isopropylamines (MAO inhibition, 5-HT decrease time course, 5-HT uptake inhibition time course. They look very neurotoxic.
(5) shows a method for 5-iodination of 2-thienyl derivatives

I heard of someone synthetizing 3-MeO-2-isopropylamino naphtalene as an DOx-analogue. It was tested up to 15 mg without noticeable effects. But a nice synthesis, starting with a perfumery compound.

Glennon wrote in (6) about 2-isopropylamino naphtalene, which has medium affinity to 5-HT2 receptors. But he gave no concrete data or refs. He somethere else wrote about it, but I can't find it at the moment. Beagle, maybe you could give us some infos.

(1) J. Pharm. Exp. Ther. 72, 265 1941
(2) J. Med. Chem. 35, 280 1992
(3) J. Pharm. Exp. Ther. ?, 807 1950
(4) J. Med. Chem. 21, 979 1978
(5) Tet. Lett. 36, 4883 1995
(6) J. Med. Chem. 30, 1 1987

Member   posted 12-07-98 01:04 PM          
Lilienthal: I have no idea how I managed to miss your reply for 2 days, but it certainly was a pleasant surprise to open this thread and find it. Thanks, I'm glad you are here!
Too bad about thienyl and furan analogs. Do you know how high a dosage was assayed. The fact that they are not valid stimulants certainly doesn't mean that methoxy analogs aren't worth looking at. I really get a thrill reading old articles like this where a chemist could synthesize a compound then describe what it tasted like after eating some him(her)self. And then go on to do self experimentation w/o being looked on as a leper.

I figured that the thienyl analog would have some toxicity. Seems pretty standard for any cpd. w/ thienyl ring.

I don't know anything about naphthyl analog that you mention, but am looking forward to checking out the refs you mention. Interesting about 3-MeO-2-naphthyl cpd.

I like the idea of the tryptamine fan club. New thread to come...

Member   posted 01-05-99 04:18 PM          
I posted the nearly complete list of references on the 4-OH-indole synthesis via 4-oxo-4,5,6,7-tetrahydrobenzofurane (4-OTHB) and 4-oxo-4,5,6,7-tetrahydroindole (4-OTHI) on the DMT-BB (DMT Related Chemistry / "my personal favorites: 4-hydroxy tryptamines" / Lilienthal 01-05-99).
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(Chief Bee)
03-15-04 14:54
No 495360
      Heterocyclic Analogs of Amphetamine
(Rated as: excellent)

Heterocyclic Analogs of Amphetamine: Thioureas, Dithiocarbamates, and Negatively Substituted Amides
William O. Foye and Suchinta Tovivich
Journal of Pharmaceutical Sciences, 68(5), 591-595 (1979) (../rhodium/pdf /heterocyclic.amphetamines.pdf)

A series of heterocyclic analogs of amphetamine was synthesized. The heterocycles employed included the 2-furyl, 2-thienyl, 3-methyl-2-thienyl, 3-pyridyl, and 6-methyl-2-pyridyl rings. The aliphatic amine group was converted to the N-methylthiourea, dithiocarbamate, methanesulfonyl, trifluoromethanesulfonyl, and trifluoroacetyl functions since similar conversions of the beta-phenethylamine structure had shown blood pressure-lowering effects and some loss of behavioral effects. p-Chlorophenyl and 1-naphthyl analogs were also converted to these derivatives. Behavioral and other biological effects, including antiarthritic, passive cutaneous anaphylactic, and antimicrobial, were observed. The 3-methyl-2-thienyl analog of amphetamine significantly increased papillary muscle contractile force without producing arrhythmias.

Anyone got this article?

Structure-activity studies on amphetamine analogs using drug discrimination methodology.
Glennon, Richard A.; Young, Richard; Hauck, Amy E.; McKenney, J. D.
Pharmacol., Biochem. Behav.  (1984),  21(6),  895-901.

The Hive - Clandestine Chemists Without Borders
(Hive Addict)
03-15-04 17:27
No 495391
      I think that the general consensus is that in...     

I think that the general consensus is that in order to maintain activity, you need to keep electron density at the aromatic nucleus, and the amine.

The aromatic ring probably binds in a hydrophobic region maybe made up of non-polar amino acid residues. When the ring works it's way in there, there is a conformational change of the receptor site, causing whatever signaling cascade to begin. When you start substituting the Benzene ring for Heterocycles, or whenever you put a hereroatom in a pi system for that matter, you start lowering the energy of the pi orbitals. This can allow for lower energy pia->pi*b donations, or sigma->pi* donation, and similar hyperconjugative effects. This kind of attraction is bad because it doesn't encourage a conformational change at the receptor. Also, as far as the nitrogen is concerned, there is most likely some H-bonding going on, which is why when you bulk it up, or make an amide, carbamate, or urea (or thio counterparts) out of it, you lose activity.
03-23-04 17:46
No 496940
      Glennon's article
(Rated as: good read)

The requested article by Glennon et al; Pharmacol., Biochem. Behav.  (1984),  21(6),  895-901


Chemistry is our Covalent Bond
04-03-04 10:06
No 498881
      How wierd...     

I was going to post a question on exactly this topic...hmm...

3-substituted thiophenes VIII 3-thienylalkylamines
JACS 76, 4466 (year?)
says that 3-thienylethylamine is about 1/3 as potent a pressor as phenethylamine.
They also state that "N-methyl beta-2-thienylethylamine and beta-2-thienylisopropylamine and it's N-methyl derivative were reported by Blicke and Burkhalter to be "semiquantitatively" similar to their phenyl analogs".
The refs are:

jacs 1942, 477 (the above)
j. pharm. exptl. therap. 1943, 187 ; 1941, 205 (pharmacological data)
USPT 2367702 has some hints on activity also.

Here is what I want, but cannot get. If some bee could retrieve some of these, it would be lovely. Some of them look very promising:

Comparative physiological actions of phenyl-, thienyl-, and furylisopropylamines. Alles, gordon A.; Feigen, Geo. A.
J. Pharmacol. (1941), 72 265-75

Phenylisopropylamine derivatives, structure, and action. van der Schoot, J. B.; Ariens, E. J.; van Rossum, J. M.(...)
Arzneimittel-Forschung (1962), 12, 902-7

Isosters and structure-similar compounds. XIII. Furylisopropylamine and other amines of the furan series. Erlenmeyer, H.; Simon, Marion.
Helvetica Chimica Acta (1941), 24 1210-13

Diet cure and hypertension. Aizawa, Toyozo; Takagi, Yasuyuki. Keio Univ. Tokyo,
Sogo Rinsho (1963), 12, 96-102

Diuretics and hypertension. Masuyama, Yoshiaki. Univ. Tokyo,
Sogo Rinsho (1963), 12, 88-95

--peace ^^

Catching a buzz @ the Hive
04-06-04 22:51
No 499472
      And doesn't anyone wonder     

Why some of these wouldn't bee decent psychedelics, for that matter? Seeing as how Nichols' potent DOB analog has furan rings, maybe a furyl psychedelic amphetamine analog would also work well.

Catching a buzz @ the Hive
(Chief Bee)
05-19-04 07:43
No 508209
      SAR: (+)-amphetamine-like discriminative stimulus
(Rated as: excellent)

Structural variation and (+)-amphetamine-like discriminative stimulus properties
Robert Oberlender and David E. Nichols
Pharmacology Biochemistry & Behavior 38(3), 581-586 (1991) (../rhodium/pdf /nichols/nichols.amphetamine-sar.pdf)

Rats were trained to discriminate (+)-amphetamine sulfate (5.43 µmol/kg, 1 mg/kg) from saline in a food-reinforced, two-lever drug discrimination paradigm. Side chain variations of the amphetamine molecular structure were analyzed for their effects on the discriminative stimulus properties of this prototype central nervous system stimulant. Partial generalization was observed for the α-ethyl homologue of (+)-amphetamine, (+)-AEPEA, and for 2-aminoindan (AI), while 5,6-methylenedioxy-2-aminoindan (MDAI) elicited only saline-appropriate responding. By contrast, 2-amino-1,2-dihydronaphthalene (ADN) and 2-aminotetralin (AT) completely substituted for (+)-amphetamine. Relative to the training drug, ADN was 1/4 as potent and AT was 1/8 as potent. The S-(-)-isomer of ADN was found to be responsible for the (+)-amphetamine-like discriminative properties of the racemate. The results suggest that constraining or extending the α-alkyl substituent of (+)-amphetamine has a deleterious effect on the ability of the resulting analogue to adopt the active conformation of (+)-amphetamine, thereby diminishing its characteristic discriminative stimulus properties.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
06-17-04 06:00
No 513951
      Potent Stimulant: 2-Amino-1,2-dihydronaphthalene     

A New, Potent, Conformationally Restricted Analogue of Amphetamine: 2-Amino-1,2-dihydronaphthalene
Bruce A. Hathaway, David E. Nichols, Maxine B. Nichols, and George K. W. Yim
J. Med. Chem. 25, 535-538 (1982) (../rhodium/pdf /nichols/nichols-2-amino-1.2-dihydronaphtalene.pdf)

A new stimulant compound, 1,2-dihydro-2-naphthalenamine (2-amino-1,2-dihydronaphthalene, 2-ADN), was prepared as an analogue of amphetamine and of 2-aminotetralin. The optical isomers of 2-ADN were obtained by chemical resolution, and the absolute configuration was determined to be R-(+) and S-(-). Preliminary pharmacological evaluation revealed that racemic 2-ADN is approximately one-fourth as potent as (+)-amphetamine as a stimulant in mice. The S-(-) isomer of 2-ADN was found to be solely responsible for the stimulant effects of the racemate. Both reserpine and α-methyl-p-tyrosine antagonized the stimulation produced by 2-ADN.

The Hive - Clandestine Chemists Without Borders