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Chromanamines: A New Group of Psychedelics?

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Youjutsu:
Until a few minutes ago, I have never heard of a chromanamine.  In fact, I doubt there is any literature on chromanamines, themselves.  I did a search on medline for the word chroman and found over 2,000 articles but none really mention anything about psychoactivity or psychedelic.  It wasn't until I drew the molecule a few months ago, not knowing then what it was, I was just thinking about the structure activity relationships of phenethylamines and also of 1,2,3,4-tetrahydro-naphthalenamines, which had interested me greatly when I discovered hallucinogenic activity had been found in them, that I realized that another group of psychedelics could be made.  After doing a IUPAC Naming on ACD/I-Lab of the structure, I found that the compound was called chroman with an amine attached in the 3rd position.  I figured the name of these compounds would be something along the line of Chromanamines.  Here is the basic structure of these Chromanamines:



Which basically looks like a 2-methoxy-phenethylamine except there is a bond between the 2-methoxy and the alpha-position which forms a ring.  Some may also say it looks like a 2-methoxy-amphetamine, in which, the carbon (methyl) is shared between the oxygen and the alpha-position.  Some obvious analogs are:



6,7-methylenedioxy-chromanamine, which is modelled after MDA.



6,7-methylenedioxy-N-methyl-chromanamine, MDMA.



6,7-dimethoxy-chromanamine, TMA-2.



6-methoxy-7-methyl-chromanamine, DOM.



7-bromo-6-methoxy-chromanamine, DOB.

Well, you get the point there are many options to explore here, and I didn't even mention any of the ALEPH series.

I guess the first question would be, does anyone know of any research that has been done on these compounds in relation to psychoactivity?  If so, references, please.  And if not, then what do you think about it's possible psychoactivity?  Do you think there are any promising compounds that can come out of this?  Also, how might these compounds be synthesized, if at all?

Thank you,

Youjutsu, Nemesis, PsiliPharm, etc...

Lilienthal:
If I remember right the Glennon group made these molecules and found them to be only modestly active at 5-HT2A receptors. But I will have a look into my references.

Youjutsu:
I wish someone would post references rather than quoting their memory which may be false.  I looked through all the references I could find and I found nothing on these Chromanamines.  I found several on Tetralins which are 5-HT1A agonists.  But I have found some sources that states that some Chromanamines have dopamine agonist properties here are the references with their abstracts:

TITLE:  Pharmacological profile of a chromanamine analogue (DP-6OH-3CA) of the selective presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin.
AUTHORS:  Vermue NA; Dijkstra D; Horn AS
AUTHOR AFFILIATION:  Department of Medicinal Chemistry, Subfaculty of Pharmacy, University of Groningen, The Netherlands.
SOURCE:  J Pharm Pharmacol 1988 Aug;40(8):574-7
CITATION IDS:  PMID: 2907015 UI: 89177999
ABSTRACT:  The pharmacological profile of an oxygen isostere of the selective presynaptic dopamine agonist DP-7OH-AT, i.e. dipropyl-6-hydroxy-3-chromanamine (DP-6OH-3CA) has been evaluated in various receptor binding, neurobiochemical and behavioural experiments. The chromanamine displaced the 3H-labelled dopamine ligands, 5,6-DPAT and N-0437, with Ki values of 106 and 143 nM, respectively. In in-vivo biochemical models for presynaptic activity the chromanamine induced a half-maximal effect in the gamma-butyrolactone reversal test at 6.8 mumol kg-1 and had an ED70 value of 40 mumol kg-1 for HVA decrease in the striatum. In behavioural models for postsynaptic dopaminergic activity a half-maximal effect for the induction of stereotypy was reached at 100 mumol kg-1 and reversal of the effects of reserpine to a level of 200 counts was induced at 11 mumol kg-1. On comparison of these results with the results obtained with the carbon analogue of DP-6OH-3CA, i.e. DP-7OH-AT, it is apparent that the chromanamine has a reduced potency for dopamine D2 receptors in in-vitro and in-vivo models. The selectivity for presynaptic dopamine receptors was lower than with DP-7OH-AT and the isomeric chromanamine, DP-8OH-3CA, indicating that the optimal position of the hydroxyl group for presynaptic selectivity is in the 8 and not in the 6 position for the chromanamines.



TITLE:  Pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine, an oxygen isostere of the dopamine agonist N,N dipropyl-5-hydroxy-2-aminotetralin with enhanced presynaptic selectivity.
AUTHORS:  Vermue NA; Kaptein B; Tepper PG; de Vries JB; Horn AS
AUTHOR AFFILIATION:  Department of Medicinal Chemistry, Faculty of Pharmacy, University of Groningen, The Netherlands.
SOURCE:  Arch Int Pharmacodyn Ther 1988 May-Jun;293:37-56
CITATION IDS:  PMID: 3421784 UI: 88339471
ABSTRACT:  The pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine (DP-8OH-3CA), the oxygen isostere of N,N dipropyl-5-hydroxy-2-aminotetralin (DP-5OH-AT), was studied and the results compared to its carbon analogue and apomorphine. The chromanamine was found to displace the D2-dopaminergic ligand [3H] 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin with a higher potency than apomorphine and DP-5OH-AT; the IC50 values were 8, 11 and 16 nM, respectively. Experiments investigating the effects of these compounds on dopamine metabolism following oral (o.a.) and intraperitoneal administration (i.p.) showed that the chromanamine had an excellent o.a./i.p. ratio. The presynaptic actions on D2-dopamine receptors, which were studied using tyrosine hydroxylase inhibition, modulation of dopamine metabolism, prevention of alpha-methyl-p-tyrosine induced dopamine depletion in rats and hypomotility in mice, showed that the chromanamine acts as a D2-agonist with half maximal effects between 0.1 and 0.4 mumol/kg (i.p.) DP-8OH-3CA was found to evoke obvious postsynaptic effects when studied in such models as stereotyped behaviour, hyperlocomotion, turning behaviour in 6 hydroxydopamine lesioned rats and reserpine reversal. Stereotypy and the accompanying hyperlocomotion were found to be induced at a half maximal dose of 17 mumol/kg (i.p.). Both with the stereotyped and turning behaviours, a long duration of action was evident. The selectivity for presynaptic receptors was found to be 6.7 times higher than that of DP-5OH-AT, indicating that oxygen substitution can cause an enhancement of selectivity for presynaptic D2-dopamine receptors. Experiments on noradrenaline release and on serotonin synthesis showed that DP-8OH-3CA had only moderate affinity for 5-hydroxytryptamine and noradrenaline receptors. It is concluded that DP-8OH-3CA is a potent D2-agonist with an excellent o.a./i.p. ratio and enhanced selectivity for presynaptic dopamine receptors.



TITLE:  6,7-Dihydroxy-3-chromanamine: synthesis and pharmacological activity of an oxygen isostere of the dopamine agonist 6,7-dihydroxy-2-aminotetralin.
AUTHORS:  Horn AS; Kaptein B; Mulder TB; de Vries JB; Wynberg H
SOURCE:  J Med Chem 1984 Oct;27(10):1340-3
CITATION IDS:  PMID: 6090664 UI: 85009643
ABSTRACT:  6,7-Dihydroxy-3-chromanamine, the oxygen isostere of 6,7-dihydroxy-2-aminotetralin (6,7-ADTN), has been synthesized and its dopaminergic activity in various test systems determined. Following bilateral injection into the rat nucleus accumbens, a pattern of locomotor activity similar to that produced by 6,7-ADTN was observed. Its ability to displace N-n-propyl[3H]norapomorphine binding to homogenates of rat brain corpus striatum was found to be about 15 times weaker than 6,7-ADTN and apomorphine. Like 6,7-ADTN it failed to influence dopamine metabolism following an intraperitoneal injection. It is suggested that in addition to the 2-aminotetralins, the 3-chromanamines may be a potential source of new dopamine receptor agonists.



TITLE:  3-Chromanamine hydrochlorides with central stimulant activity.
AUTHORS:  Lockhart IM; Foard SA
SOURCE:  J Med Chem 1972 Aug;15(8):863-5
CITATION IDS:  PMID: 5044309 UI: 72235357


I haven't checked out any of these sources since I've just found them about 5 minutes ago.  I definitely want to check out this last one.

-Youjutsu

ScuzZ:
Dude if you reseached all that in just 5 mins you're a genius(close to it)

Youjutsu:
No, I'm not a genius...I just searched medline for "chromanamine"...which took about 5 minutes...and then I copied what I found and pasted it here...I haven't actually had time to check these sources out...but I do plan on it.

-Youjutsu

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