Author Topic: Ariadne and the Butanamines  (Read 3617 times)

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Ariadne and the Butanamines
« on: November 16, 2003, 09:39:00 PM »
This is a digest on the butanamine family, compounds that are related to Ariadne in Pihkal.

I. - Intro: What is a butanamine?

Every good bee know what is a phenethylamine (2 carbon side chain ie: ethyl as in ethylamine) as well as an amphetamine (alpha-methyl-phenethylamine, with a three carbon aminated side chain: isopropylamine or 2-propylamine).

Phenethylamine :


PEA ("NCCc1ccccc1")

Amphetamine :


A ("CC(N)Cc1ccccc1")

Those backbone skeletons have to be properly substituted to make more interesting materials, giving birth to entheogenic compounds as in 2,4,5- or 3,4,5- substitution patterns, or also empathogenic ones like in the 3,4-methylenedioxy- pattern.

Examples of the 2,4,5- pattern:



2C-D ("COc1cc(CCN)c(OC)cc1C")



DOM ("COc1cc(CC(C)N)c(OC)cc1C")

Examples of the 3,4,5- pattern:



M ("COc1cc(CCN)cc(OC)c1OC")



TMA ("COc1cc(CC(C)N)cc(OC)c1OC")

Examples of the 3,4-methylenedioxy- pattern:



MDPEA ("NCCc2ccc1OCOc1c2")



MDA ("CC(N)Cc2ccc1OCOc1c2")

In general a phenethylamine is weaker than the corresponding amphetamine. For instance 2C-D is reported in Pihkal to have an active dose of 20-60mg vs DOM which is active at 3-10 mg. MDPEA is considered inactive (having a potency lower than mescaline) but MDA is active.

Those side chains are well known, and most PEA like compounds belong to either family. But there is a further side chain modification that has been done: homologation to the four-carbons side chain derivative, ie to the 2-butylamine, to form the butanamine family.

Straight butanamine:


B ("CCC(N)Cc1ccccc1")

Ariadne (4C-DOM):


Ariadne ("CCC(N)Cc1cc(OC)c(C)cc1OC")



AEM ("CCC(N)Cc1cc(OC)c(OC)c(OC)c1")



MBDB ("CCC(N)Cc2ccc1OCOc1c2")

I will discuss about the Ariadne analogs here, which have the favorable 2,4,5-substitution pattern on the ring. The 3,4,5- compounds are not potent enough and were not further researched than AEM, the alpha-ethyl homologue of mescaline which is deemed inactive. MBDB is not my cup of tea.

II. - Meet the lovely Ariadne

Let me quote a brief excerpt of its

Pihkal entry

( first:

This compound, to which I had given the name of ARIADNE as the first of my ten "classic ladies" (I'll say more about them later), was not really a stimulant of any kind, certainly it was not a psychedelic, and yet there was something there. It had been explored rather extensively as a potential psychotherapeutic ally by a friend of mine. He said that there seemed to be some value in a few of his patients who had some underlying depression, but not much of anything with the others. So, I decided to call it an anti-depressant. I had mentioned some of this history one time when I was giving an address at a conference on the East Coast, and my host (who happened to be the research director at a large pharmaceutical house) asked if I would send him a sample. His company did many animal tests, one of which showed that it was not hallucinogenic (a cat whose tail erected dramatically with DOM did nothing with ARIADNE) and another that showed re-motivation (some old maze-running monkeys who had decided not to run any more mazes changed their minds with ARIADNE).

III. - Related references:

Inhibition of axoplasmic transport by mescaline and other trimethoxyphenylalkylamines.
Paulson, James C.; McClure, William O.
Molecular Pharmacology  (1973),  9(1),  41-50.


Intraocular injection of mescaline-HCl (I-HCl) [832-92-8] (0.1-1 mg), 1-(3,4,5-trimethoxyphenyl)-2-aminopropane-HCl (II) [5688-80-2], or 1-(2,4,5-trimethoxyphenyl)-2-aminopropane-HCl (III) [15995-72-9] inhibited the axoplasmic transport of labeled proteins from the ganglion cells of the retina through the optic nerve in rats.  The inhibition of fast axoplasmic tranpsort produced by I in the rat optic system was reversible.  I inhibited transport in the cat sciatic nerve.  However, the component pieces of the mol. structure of I, mixts. of trimethoxybenzene and ethylamine, did not inhibit fast axoplasmic transport in either the rat optic or cat sciatic nerves.  The rank order of the hallucinogenic potencies of the drugs and their effectiveness as antitransport agents was the same and was III > II > I.

Cardiovascular and gross behavioral effects of amphetamine, 2-amino-1-(2,5-dimethoxy-4-methylphenyl) propane(DOM), and 2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A) in the conscious dog.
Buyniski, J. P.; Smith, M. L.; Bierwagen, M. E
Communications in Chemical Pathology and Pharmacology  (1974),  8(2),  213-21.


The i.v. administration of increasing doses of amphetamine sulfate [60-13-9] (0.1-3 mg/kg), R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)propane-HCl (DOM)(I) [50505-88-9] (0.1-1 mg/kg), and BL-3912A (R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane-HCl)(II) [52663-86-2] (0.1-5 mg/kg) to conscious beagle dogs resulted in appreciable gross behavioral and cardiovascular changes.  Gross behavioral changes ranged from stereotyped activity and disorientation with amphetamine to cationia with DOM and brief central nervous system stimulation with BL-3912A.  In conscious dogs, all three drugs raised mean aortic blood pressure, with amphetamine being the most effective (62 mm Hg) followed by DOM (48 mmHg), and BL-39121A (41 mm Hg).  Heart rate was consistently reduced only by amphetamine.  BL-3912A resulted in depressor responses on blood pressure in anesthetized dogs and this suggests that in the conscious dog BL-3912A may be activating centers in the central nervous system to effect a pressor response.  The elevation of blood pressure in the conscious dog induced by amphetamine and DOM is mediated, at least in part, via their peripheral actions.

Phenylalkylamines with potential psychotherapeutic utility.  1.  2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
Standridge, Robert T.; Howell, Henry G.; Gylys, Jonas A.; Partyka, Richard A.; Shulgin, Alexander T.
Journal of Medicinal Chemistry  (1976),  19(12),  1400-4.


Title compd. (+-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane-HCl (I-HCl) [54690-19-6] was prepd. by condensation of 2,5-dimethoxy-4-methylbenzaldehyde [4925-88-6] with 1-nitropropane followed by redn., and the product resolved into the (S)- [(S)-I-HCl] [52918-31-7] and (R)-isomer [(R)-I-HCl] [52663-86-2].  2,5-Dimethoxy-4-methylphenethylamine-HCl (II-HCl) [25505-65-1] was prepd. by redn. of the corresponding phenylacetonitrile deriv.  Pharmacol. activity differences are shown between the isomers of I, amphetamine [300-62-9], II, and (S)-DOM [(S)-III] [43061-14-9] and (R)-DOM [(R)-III] [43061-13-8].  There was no significant potency difference between (S)-I and (R)-I in serotonergic effects on smooth muscle, but (R)-III was approx. twice as active as (S)-III in this test.  In the rabbit hyperthermia test (R)-III had 25-100 times the potency of the isomers of I, while II had intermediate activity.  Acquisition of the avoidance response by rats was facilitated by (R)-I.  Structure-activity relations are discussed.     

Comparison of the effects of R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)propane (DOM), R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane (BL-3912A) and 5-hydroxytryptamine on non-innervated vascular smooth muscle.
Dyer, Donald C.
Research Communications in Chemical Pathology and Pharmacology  (1976),  14(3),  449-54.


Isolated strips of sheep umbilical arteries contracted in the presence of BL-3912A [R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane-HCl](I) [52663-86-2] (10-5 x 10-8 M).  These contractions faded over an hr period and at this time I (>10-6 M) antagonized contractions to R-(-)-DOM [50505-88-9], 5-hydroxytryptamine (5-HT) [50-67-9] but not to angiotensin [1407-47-2].  The initial contraction produced by I was antagonized by cinanserin, a 5-HT antagonist.  These expts. indicate that I can be classified as a partial agonist of 5-HT receptors in sheep umbilical arteries.

Behavioral comparisons of R-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A) with R-DOM and S-amphetamine.
Tilson, H. A.; Chamberlain, J. H.; Gylys, J. A.
Psychopharmacology (Berlin, Germany)  (1977),  51(2),  169-73.


The behavioral effects of BL-3912A R-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane HCl)(I) [52663-86-2] were compared with those of (S)-amphetamine sulfate [51-63-8] and (R)-DOM [R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)propane-HCl] [50505-88-9].  I facilitated acquisition of shuttle box responding by rats without increasing noncontingent intertrial (ITI) activity, while (S)-Amphetamine increased both avoidance and ITI responding.  (R)-DOM had a biphasic effect on avoidance responding, increasing it at low doses and disruptiing at higher doses.  At doses that facilitated shuttle box responding, I had no effect on unacclimated motor activity of rats nor on the rate of continuous avoidance responding by rats.  (S)-Amphetamine increased the frequency of both motor activity and operant avoidance responding, while (R)-DOM decreased motor activity and increased operant avoidance responding.  By facilitating avodiance behavior without increasing other measures of psychomotor activity, I represents a unique psychopharmacol. agent clearly different from (R)-DOM and (S)-Amphetamine. 

Further studies on BL-3912A:  effects on avoidance behavior of rats with low baselines and on reaction thresholds to electric footshock.
Tilson, Hugh A.; Chamberlain, John H.; Gylys, Jonas A.
Pharmacology, Biochemistry and Behavior  (1977),  6(6),  627-30.


BL 3912A (I)  [52663-86-2] (5 and 10 mg/kg, i.p.) given to rats increased the no. of avoidance responses without affecting responses during the intertrial interval (ITI).  Statistically reliable effects on behavior were not obsd. following 20 mg I/kg.  (S)-amphetamine at 0.5 and 1 mg/kg i.p. also facilitated avoidance responding, but could be differentiated from I in that the (S)-amphetamine significantly increased shuttles during the ITI.  (S)-amphetamine at 0.1 mg/kg was not effective, whereas 2 mg/kg increased ITI activity.  Piracetam (50 or 200 mg/kg) had no significant effects on avoidance or shuttles during ITI.  Using an elec. shock titrn. procedure, I at 10 or 20 mg/kg i.p. had no significant effect on reaction thresholds.  Animals receiving 100 mg/kg of p-chlorophenylalanine orally for 3 days and tested 2 days later showed hyperalgesia to the elec. shock.  Thus, I facilitated shuttle box avoidance responding of rats with low performance baselines.  Behavioral facilitation occurred without concomitant increases in noncontingent activity or apparent changes in reactivity to elec. footshock. 

Synthesis and body distribution of several iodine-131-labeled central nervous system active drugs.
Braun, Ulrich; Shulgin, Alexander T.; Braun, Gisela; Sargent, Thornton, III.
Journal of Medicinal Chemistry  (1977),  20(12),  1543-6.


Iodine-131 labeled compds. I [64584-34-5], II [64584-32-3], and III [64584-33-4] were prepd. from the appropriate phthalimide deriv. by reaction with iodine-131-labeled ICl, followed by hydrazinolysis.  Body distribution studies in the dog and the rat showed concns. of I and II in the dog brain and the rat lung and liver which would be of use in scintigraphy.

Evaluation of substituted-amphetamine hallucinogens using the cat limb flick model.
Rusterholz, D. B.; Spratt, J. L.; Long, J. P.; Barfknecht, C. F.
Communications in Psychopharmacology  (1977),  1(6),  589-92.


I.p. administration of 0.1 mg/kg of (+-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-HCl (I-HCl)  [29243-80-9] or R-(-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane-HCl  [50505-92-5], or 1.0 mg/kg of (+-)-1-(2,5-dimethoxyphenyl)-2-aminopropane-HCl  [16094-57-8] increased the no. of cat limb flicks during a 1 h observation period.  S-(+)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane-HCl  [50505-93-6] and (+-)-1-(2,5-dimethoxy-4-ethylphenyl)-2-aminopropane-HCl  [53581-54-7] (0.1 mg/kg, i.p.) increased the no. of flicks obsd. but not significantly.  The alpha-Et analog of I, BL3912A  [52663-86-2], produced almost no increase in flick responding.  These results confirm the usefulness of this model for studying hallucinogens of the amphetamine type. 

Synthesis and turnover of 3H-5-hydroxytryptamine in the lateral cerebroventricle.    
Kantak, K. M.; Wayner, M. J.; Tilson, H. A.; Dwoskin, L. P.; Stein, J. M.
Pharmacology, Biochemistry and Behavior  (1978),  8(2),  153-61.


The lateral cerebroventricle was perfused, using 2 different labeling procedures in expts. on 5-hydroxytryptamine  [50-67-9] metab. in rat brain.  The sensitivity of 5-hydroxytryptamine metab. to various drugs was subsequently detd.  Two serotonin reuptake blockers, imipramine-HCl  [113-52-0] and fluoxetine-HCl  [56296-78-7], increased the efflux of 5-hydroxytryptamine-3H into the ventricle without affecting the efflux of labeled 5-hydroxyindoleacetic acid.  BL-3912 A  [52663-86-2], a drug with weak serotonin-agonist activity, also increased the efflux of 5-hydroxytryptamine-3H into the ventricle.

Phenylalkylamines with potential psychotherapeutic utility.  2.  Nuclear substituted 2-amino-1-phenylbutanes.
Standridge, Robert T.; Howell, Henry G.; Tilson, Hugh A.; Chamberlain, John H.; Holava, Henry M.; Gylys, Jonas A.; Partyka, Richard A.; Shulgin, Alexander T.
Journal of Medicinal Chemistry  (1980),  23(2),  154-62.


A series of 28 I [mostly racemic or (R) isomers] was prepd. and tested as performance enhancing agents, esp. avoidance-response acquisition; most of the compds. had low hallucinogenic potential.  Compds. prepd. included I (R = H, Me, Et, Me2CH, MeS, Pr, Bu, OH, EtO, PrO, Me2CHO, NO2, NH2, Cl, Br, iodo).

Effects of the phenethylamine derivatives, BL-3912, fenfluramine, and Sch-12679, in rats trained with LSD as a discriminative stimulus.
Winter, J. C.
Psychopharmacology (Berlin, Germany)  (1980),  68(2),  159-62.


Rats were trained to discriminate the effects of LSD tartrate  [17676-08-3] (100 ?g/kg) and saline in a 2-lever choice task.  They were then tested with each of 3 phenethylamine derivs., BL-3912A (I)  [52663-86-2], fenfluramine-HCl (II-HCl)  [404-82-0], and Sch-12679 (III)  [39624-66-3].  II and III yielded intermediate results, i.e., responding was not fully appropriate for either training condition, whereas I substituted completely for LSD.  The LSD-like effects of each of the drugs were antagonized by pretreatment with BC-105, a serotonergic antagonist known to block the stimulus effects of indole and phenthylamine hallucinogens.  These data, together with I-III, indicated that (1) a variety of drugs may substitute in whole or in part for LSD in LSD-trained rats, and (2) even complete substitution of a drug for LSD in the rats is not necessarily assocd. with the prodn. by that drug of hallucinations in man. 

Indolealkylamine and phenalkylamine hallucinogens.  Effect of alpha-methyl and N-methyl substituents on behavioral activity.
Glennon, Richard A.; Young, Richard; Jacyno, John M.
Biochemical Pharmacology  (1983),  32(7),  1267-73.


Animals (rats), trained to discriminate the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM)  [15588-95-1] from saline in a 2-lever operant procedure, were challenged with various doses of several indolealkylamines and phenalkylamines.  In both series, the alpha-Me analogs were more active than either their N-Me or alpha-demethyl counterparts.  Furthermore, when the activities of the optical isomers of DOM were compared with the activities of S-(+)  [7795-51-9] and R-(-)-alpha-methyltryptamine (alpha-MeT)  [7795-52-0], the more potent isomer of alpha-MeT (i.e. S) possessed the opposite abs. configuration of the more potent isomer of DOM (i.e. R).  With respect to the mechanism of action of these agents, these findings are not inconsistent with a common site hypothesis. 

Comparison of stimulants and hallucinogens on shuttle avoidance in rats.
Davis, W. M.; Hatoum, H. T.
General Pharmacology  (1987),  18(2),  123-8.


Rats were trained to a high level of performance of a conditioned avoidance response in a shuttlebox to test effects of several classical stimulants in comparison to a variety of hallucinogens.  A previously-reported biphasic pattern of effects of mescaline  [54-04-6] on shuttle avoidance was replicated and extended to 12 other hallucinogens of both phenylethylamine and indolealkylamine classes.  Response patterns of hallucinogens could be differentiated from 3 stimulants and from a methoxyamphetamine compd. that lacks hallucinogenic activity.

MDMA-like stimulus effects of alpha-ethyltryptamine and the alpha-ethyl homolog of DOM.
Glennon, Richard A.
Pharmacology, Biochemistry and Behavior  (1993),  46(2),  459-62.


One-C homologation of phenylaklylamine or indolylaklylamine hallucinogens contg. an alpha-Me substituent typically results in a redn. of hallucinogenic potency; however, this same structural change has little to no effect on agents that produce MDMA-like effects.  Rats trained to discriminate 1.5 mg/kg of MDMA (3,4-methylenedioxymethamphetamine) from saline vehicle were employed to det. if the alpha-Et homologs of the hallucinogens 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and alpha-methyltryptamine (alpha-MeT) - i.e., alpha EH DOM (BL-3912) and alpha-ethyltryptamine (alpha-EtT), resp. - would produce stimulus effects similar to those of MDMA.  Although the MDMA stimulus failed to generalize to DOM (previously published) and alpha-MeT (this study), MDMA stimulus generalization occurred both to alpha-EH DOM (ED50 = 1.3 mg/kg) and alpha-EtT (ED50 = 3.5 mg/kg).  A (+)-amphetamine stimulus (training dose = 1.0 mg/kg) only partially generalized to these 2 agents, suggesting that the MDMA stimulus generalization involves more than a simple amphetamine-like action.  As such, this is the 1st demonstration that classical hallucinogens can produce MDMA-like effects upon homologation and that MDMA-like stimulus effects can be assocd. with an indolylaklylamine.  Also, these results continue to support the concept that an intact methylenedioxy ring system, such as that found in MDMA and other MDMA-related agents, is not a structural requirement for drugs to produce MDMA-like effects.

IV.b - Patents:

Compounds for improving the capacity for intellectual work of mammals.
1974, 19 pp.

Patent FR2205330

2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane isomers with learning capacity increasing effect.
1974, 30 pp.

Patent DE2355350

1977, 7 pp.

Patent US4034113

1978, 10 pp.

Patent US4105695

Improvements in the enzymatic synthesis of chiral amines.
1999, 14 pp.

Patent WO9946398