Author Topic: Chromanamines: A New Group of Psychedelics?  (Read 1798 times)

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Youjutsu

  • Guest
Chromanamines: A New Group of Psychedelics?
« on: July 01, 2000, 01:25:00 PM »
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

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Re: Chromanamines: A New Group of Psychedelics?
« Reply #1 on: July 02, 2000, 12:40:00 AM »
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

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #2 on: July 03, 2000, 12:29:00 AM »
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

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #3 on: July 03, 2000, 05:45:00 AM »
Dude if you reseached all that in just 5 mins you're a genius(close to it)


Youjutsu

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #4 on: July 03, 2000, 07:26:00 AM »
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


Lilienthal

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #5 on: July 03, 2000, 02:21:00 PM »
Sorry, the Glennon article was about amino-analogs of chromanes (tetrahydrochinolines).

[edited]
Hit me, I was wrong again. That paper was about tetrahydroisochinolines not related to your chromanes.
[/edited]

But here are some chemistry references directly from Beilstein:

Bioorg. Med. Chem. 7: 335 (1999): 6-methoxy-3-amino-chromane
J. Org. Chem. 63: 5362 (1998): (R)/(S)/(R/S)-3-aminochromane
Pharm. Pharmacol. Commun. 1: 47 (1998): 6,7-ethylendioxy-3-amino-chromane
Eur. J. Med. Chem.Chim.Ther. 26: 497 (1991):5-methoxy-3-amino-chromane, 6,7-dimethoxy-3-amino-chromane, 7-methoxy-3-amino-chromane



Lion

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #6 on: July 03, 2000, 07:30:00 PM »
Interesting stuff to theorize about... very structurally similar to 2-aminotetralin. 

Be aware... 2-aminotetralin is a very nasty nasty compound.  That goes for 2-aminoindane also...

It's quite aasy to be fooled by the animal data and binding studies.  Extrapolating data to humans
is very tricky bizness, and many times it's simply not the same.  Contrary to what the Nichols and Glennon studies point towards, the tetralin compound is nothing at all like amphetamine.  It's ten billion universes in the opposite direction. 

Don't go there girlfriend!

Best Regards,

The Lion


Youjutsu

  • Guest
Re: Chromanamines: A New Group of Psychedelics?
« Reply #7 on: July 03, 2000, 11:37:00 PM »
How do you connect to Beilstein?  What server do you use?  I've used the program before and I couldn't figure out how to use it, but I don't think I messed with it for more than a few minutes.

I've found some other interesting references:

TITLE:  5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.
AUTHORS:  Simon P; Guardiola B; Bizot-Espiard J; Schiavi P; Costentin J
AUTHOR AFFILIATION:  Unite de Neuropsychopharmacologie, U.R.A. 1170 du C.N.R.S., Faculte de Medecine et Pharmacie de Rouen, Saint Etienne du Rouvray, France.
SOURCE:  Psychopharmacology (Berl) 1992;108(1-2):47-50
CITATION IDS:  PMID: 1357709 UI: 93029100
ABSTRACT:  The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] decane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.


TITLE:  Enhancement of cortical and hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by BAY x 3702 in freely moving rats.
AUTHORS:  Koyama T; Nakajima Y; Fujii T; Kawashima K
AUTHOR AFFILIATION:  Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan.
SOURCE:  Neurosci Lett 1999 Apr 9;265(1):33-6
CITATION IDS:  PMID: 10327199 UI: 99257131
ABSTRACT:  Involvement of serotonin (5-HT) in the regulation of cholinergic neuronal activity by modulation of acetylcholine (ACh) release has been reported for various regions of the brain. Cortical and hippocampal cholinergic neurotransmission is of particular importance in the mechanisms of attention as well as learning and memory. In the present study, we investigated the effect of R-(-)-2-[4-[(chroman-2-yl-methyl)-amino-butyl]-1,1-dioxo-benzo[d]++ +isothiazolone hydrochloride (BAY x 3702), a novel, high-affinity 5-HT1A receptor agonist, on ACh release in the cerebral cortex and hippocampus of freely moving rats using an in vivo microdialysis technique. Acetylcholine efflux from the cortex and hippocampus was measured every 30 m using a sensitive and specific radioimmunoassay and was stable for at least 5 h. The ACh efflux from the cortex and hippocampus was increased significantly by BAY x 3702 (0.3 mg/kg, i.p.) compared with saline administration. WAY-100635 (0.6 mg/kg, s.c.), a selective 5-HT1A receptor antagonist, eliminated the augmentation of ACh efflux induced by BAY x 3702 in both brain regions. These results demonstrate that stimulation by BAY x 3702 enhanced ACh release in both the cortex and hippocampus through 5-HT1A receptor-mediated pathways.


TITLE:  Discriminative stimulus properties of the 5-HT1A receptor agonist BAY x 3702 in the rat.
AUTHORS:  De Vry J; Jentzsch KR
AUTHOR AFFILIATION:  CNS Research, Bayer, Cologne, Germany. jean.vry.jv@bayer-ag.de
SOURCE:  Eur J Pharmacol 1998 Sep 11;357(1):1-8
CITATION IDS:  PMID: 9788767 UI: 99002816
ABSTRACT:  The aminomethylchroman derivative BAY x 3702 (R-(-)-2-4-[(chroman-2-ylmethyl)-amino]-butyl-1,1-dioxo-benzo[d] isothiazolone HCl) has recently been characterized as a relatively selective, high affinity 5-HT1A receptor agonist with neuroprotective, anxiolytic- and antidepressant-like effects in animal models. It was the aim of the present study to further confirm its receptor binding profile in an in vivo assay. Rats were trained to discriminate BAY x 3702 (0.1 mg/kg, i.p.) from vehicle in a standard two-lever fixed ratio 10 food-reinforced procedure. All rats learned the discrimination, the median number of sessions to reach criterion being 38 (range: 22-58 sessions). Generalization tests with BAY x 3702 showed dose-dependent and complete generalization after different routes of administration; the ED50 values being: 0.030, 0.007 and 0.36 mg/kg, after i.p., i.v. and p.o. administration, respectively. Assessment of the duration of action after administration of 0.1 mg/kg BAY x 3702, i.p., resulted in a T1/2 of 65 min. Dose-dependent and complete generalization was also obtained with the 5-HT1A receptor agonists 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin, ED50 in mg/kg, i.p.: 0.086), flesinoxan (0.30), SR 57746A ((4-(3-trifluoromethylphenyl)-N-(2-(naphth-2-yl)ethyl)-1,2,3,6-tet rahydropyridine HCl, 1.0), the (+)-enantiomer of BAY x 3702 (1.3) and ipsapirone (1.8); the ED50 values being closely correlated with their respective affinities for the 5-HT1A receptor. Pretreatment with the selective 5-HT1A receptor antagonist WAY-100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N(2-pyridinyl) cyclohexane carboxamide trihydrochloride) dose-dependently and completely blocked the discriminative effects of 0.1 mg/kg BAY x 3702 (ID50: 0.013 mg/kg, i.p.). WAY-100635, prazosin, idazoxan, raclopride, paroxetine, (-)-BAY k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-p yridine-5-carboxylate), ethanol, and the putative neuroprotectants MK-801 ((+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e), CNS 1102 (N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methyl-guanidine), CGS 19755 (cis-4-(phosphonomethyl) piperidine-2-carboxylic acid) and nimodipine did not induce more than 20% generalization. It is concluded that the BAY x 3702 cue is mediated by its agonistic activity at 5-HT1A receptors.


TITLE:  Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist.
AUTHORS:  De Vry J; Schohe-Loop R; Heine HG; Greuel JM; Mauler F; Schmidt B; Sommermeyer H; Glaser T
AUTHOR AFFILIATION:  CNS Research, Troponwerke GmbH & Co. KG, Cologne, FRG.
SOURCE:  J Pharmacol Exp Ther 1998 Mar;284(3):1082-94
CITATION IDS:  PMID: 9495870 UI: 98173751
ABSTRACT:  The aminomethylchroman derivative BAY x 3702 (R-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d] isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT)1A receptor ligand [calf hippocampus: Ki: 0.19 nM; reference compounds 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT1A receptors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relatively high to moderate affinity to the following receptors: alpha-1 and alpha-2 adrenergic (Ki: 6 and 7 nM, respectively); 5-HT7- and 5-HT1D (7 and 36 nM); dopamine D2- and D4 (48 and 91 nM); sigma sites (176 nM) and 5-HT2C (310 nM); others: > 10 microM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonist (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide trihydrochloride (WAY-100635). At those receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D receptors) or an antagonist (alpha-1, alpha-2 and D2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY x 3702 (0.5 microgram/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY x 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY x 3702 (ED50: 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY x 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED50: 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with high potency and intrinsic activity.


TITLE:  Cycloaddition of dichloroketene to N,N-disubstituted 3-aminomethylene-5-hydroxy-2,2-dimethyl-7-pentyl-4-chromanone: synthesis of 2H,5H-pyrano[3,2-c][1]benzopyran derivatives.
AUTHORS:  Cafaggi S; Romussi G; Ciarallo G; Bignardi G
SOURCE:  Farmaco [Sci] 1983 Oct;38(10):775-83
CITATION IDS:  PMID: 6139296 UI: 84058312
ABSTRACT:  The synthesis of N,N-disubstituted 3-aminomethylene-5-hydroxy-2,2-dimethyl-7-pentyl-4-chromanones (III) and their reaction with dichloroketene are described. The resulting cycloadducts (IV) gave, by dehydrochlorination, the N,N-disubstituted 4-amino-3-chloro-10-hydroxy-5,5-dimethyl-8-pentyl-2H,5H-pyrano[3,2-c] [1]benzopyran-2-ones (V), which are structurally related to tetrahydrocannabinols. Only the compound (V a) displayed a very weak stimulant activity on the CNS.


TITLE:  Stereoselective synthesis of cis- and trans-3-amino-4-chromanols.
AUTHORS:  Sugihara H; Sanno Y
SOURCE:  Chem Pharm Bull (Tokyo) 1977 May;25(5):859-66
CITATION IDS:  PMID: 45506 UI: 87187845


Well, that's just about all I could find that was even remotely interesting.

Laters,

Youjutsu, Nemesis, PsiliPharm, etc...