General
The Future Synthetic Drugs Of Abuse
Designer Drugs - part 2 of 3
By Donald A. Cooper
From The DEA
Indolealkylamines
All of the hallucinogenic indolealkylamines can be classified as belonging to the family of compounds known as tryptamines and are substituted 3-(2-ethylamino)indoles.
The tryptamines are a most interesting and biologically useful class of compounds. In the human body, serotonin (5-hydroxytryptamine) functions as a vasoconstrictor, inhibits gastric secretion, stimulates smooth muscle, and is naturally present in the central nervous system where it is involved in neurotransmission (Goodman and Gilman 1970).
The 5-methoxy homolog of serotonin is considered to be hallucinogenic in humans as is the 5-methoxy homolog of gramine (3-(N,N-dimethylaminomethyl)indole) (Gessner et al. 1961). Melatonin (N-acetyl-5-methoxytryptamine), formed by the mammalian pineal gland, appears to depress gonadal function and is known to cause contractions of melanophores.
Bufotenine, the N,N-dimethyl homolog of serotonin, is classified as a very weakly active hallucinogen and is noted to have extremely unpleasant cardiovascular depressive side effects (Holmstedt et al. 1967).
The O-methyl homolog of bufotenine, N,N-dimethyl-5-methoxytryptamine (5-methoxy-DMT), is reported to be an extremely potent hallucinogen, but it, like all other C-5 substituted indolealkylamines, is not active if taken by mouth (Brown 1972).
Both DMT and DET are well known for their hallucinogenic activity, just as both of these compounds are also inactive if taken by mouth.
The N,N-dipropyl and diallyl derivatives are also hallucinogenic only if used either parenterally or by inhalation at approximately the same level as DET, whereas higher homologs abruptly become inactive (Szara and Hearst 1962).
The compound 6-hydroxy-DET has been determined to be a major metabolite of DET in man (Szara et al. 1966), and it does not possess hallucinogenic activity (Szara 1970).
Conversely, the 4-hydroxy-N,N-dimethyltryptamines (psilocin and psilocybin), are very active hallucinogens when taken orally.
The activity of psilocybin (O-phosphoryl-4-hydroxy-DMT) when taken by mouth is not related to the phosphoric acid radical since the pharmacological effects of psilocin (4-hydroxy-DMT) are identical (Horita and Weber 1961).
Pharmacological information for baeocystin (4-hydroxy-N-methyltryptamine) was not found; however, one would expect hallucinogenic activity to parallel that of the N-alkyl-tryptamines and thereby would expect the drug to be weakly hallucinogenic.
It is thought that in the past most clandestine syntheses of indolealkylamines used indole as the starting material (Speeter and Anthony 1954).
A modest literature search will convince a clandestine chemist that the use of the Fischer indole synthesis affords access to a greater variety of indole derivatives (Huisgen and Lux 1960; Robinson 1983) as it will also reduce the chance that law enforcement will be alerted by his purchases of essential chemicals.
Hence, in the production of indolealkylamine derivatives, the covert chemist need not be limited by the commercial availability of appropriate indole precursors.
Relative to those which lack an aryl ring substitution, there is no doubt that the activity of psilocybin/psilocin upon ingestion is due to an enhancement of gastrointestinal absorption which, in turn, must be structurally related to the presence of the C-4 hydroxyl substitution.
Therefore, if the CsA amendment were not a consideration, derivatives derived from psilocin would be the obvious first choice. These derivatives are the 4-hydroxy-N,N-alkyl homologs starting with N,N-dimethyl, N,N-methyl-ethyl, and on to N,N-diallyl to give a total of 10 possible derivatives.
As is also the case for hallucinogenic phenylalkylamines, alkyl substitution, not to exceed a C-3 moiety, at the position alpha to the side chain nitrogen generally will maintain hallucinogenic activity.
This brings the total possible number of hallucinogenic CsA's of psilocin to 40. A somewhat removed second choice would be the same series of derivatives in conjunction with either acetylation or methylation of the indole nitrogen.
This would then bring the total number of the possible 4-hydroxy substituted tryptamine CsA's (less one for psilocin) to 119.
The 5-methoxy derivatives of gramine and serotonin are first choices for future CsA's when considering the new U. S. amendment. Substitution at the alpha carbon on the side chain will probably maintain psychotropic activity only for serotonin derivatives.
Hence, allowing only a methoxy substituent at the aryl C-5 position, and a substitution at the carbon alpha to the nitrogen (the nitrogen being any combination of hydrogen, methyl, ethyl, n-propyl, and allyl) 75 CsA's can be obtained.
Then substitution of the indole nitrogen with either methyl or acetyl brings the total number of possible CsA's that can be argumentatively related to serotonin to 225.
An additional series of compounds that could serve as future CsA's under U. S. law are those which are substituted with alkyl groups at the carbon alpha to the side chain nitrogen.
Recently, a commercially available tryptamine which has an ethyl moiety substituted at the alpha carbon has become the newest U.S. tryptamine CsA.
Known as ET in the illicit CsA drug market is 3-(2-amino-butyl)indole (etryptamine, monase by Upjohn (Kalamazoo, MI)).
Because ET does not appear in either Schedule I or II of the CFR and is a legally marketed product, ET and derivatives thereof are exempted from control under the CsA amendment.
Pharmacokenitic data on ET indicates that it is a monoamine oxidase inhibitor (Govier et al. 1953; Klein and Davis 1969) and psycho-energizer (Robie 1961; deHaen 1964). Hence, ET could produce some degree of hallucinogenic activity in man.
In 1986 ET was reported as the she causative agent in a fatal overdose in Duesseldorf, Germany (Daldrup et al. 1986). This may be one of the few times that a CsA has originated outside of the U. S.
The sample of ET which was submitted to our laboratory appears to have been obtained from the Aldrich Chemical Company ($48.05/100 gm; Milwaukee, WI).
Unfortunately, it is not yet clear if ET is actually the substance which is producing the biological response being sought by the illicit user.
It is the case that the sample of ET we examined and the batch of ET which the Aldrich Chemical Company is presently selling contains a major quantity (about 30%) of the agent which could also be a hallucinogen (Turner 1963; Naranjo 1967).
Nomenclature for this possible hallucinogen can either be 1-methyl-3-ethyl-1,2,3,4-tetrahydro-harmane, or 2,2-dimethyl-4-ethyl-2,3,4,5-tetrahydro-[beta]-carboline.
The creation of this substance most probably occurred after synthesis and during the purification of ET.
Under anhydrous conditions, the reaction of acetone and ET would give the corresponding enamine which could then undergo a Mannich condensation to yield the hallucinogen (Whaley and Govindachari 1951; Shoemaker et al. 1979).
The compound 2-methyl-8-methoxy-4,5-dihydro-[beta]-carboline (harmaline) is considered to be a hallucinogen (Hochstein and Paradies 1957) as well as a monoamine oxidase inhibitor (Burger and Nara 1965).
On the other hand, the compound 2-methyl-8-methoxy-2,3 4,5-tetrahydro-[beta]-carboline is classified as a tranquilizer (Usdin and Efron 1972). We were not able to attain any literature whatsoever on the hallucinogen shown in compound 4, much less any pharmacokenetic data.
Hence, due to the apparently unpredictable pharmacological behavior of structurally similar [beta]-carboline derivatives, I will not speculate as to the pharmacological properties of said substance.
Phenylalkylamines
As was observed for the simple indole alkaloids, there are several simple phenylalkylamines which play important roles in the normal biological function. Some of these are tyrosine, 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxytryptamine (dopamine), and norepinephrine.
The naturally occurring hallucinogenic protoalkaloid, mescaline, is 2-(3,4,5-trimethoxyphenyl)ethylamine. Structural modifications which impart hallucinogenic activity to phenylethylamines have been studied and a considerable quantity of that data is easily retrieved.
The following constitutes a brief review of some of the most salient concepts relative to hallucinogenic activity chemical structure relationships within the family of phenylethylamine derivatives.
It has been found that the addition of methoxy moieties to the aromatic ring of a phenylethylamine, in general, produces compounds that are psychotomimetic (Shulgin et al. 1969).
Further, it has been noted that the methylenedioxy moiety can be used in the place of two adjacent ring substituted methoxy groups with C-3,4 substitution providing the most potent psychotogens (Alles 1959; Shulgin 1964; Naranjo et al. 1967; Braun et al. 1980a).
Historically 3,4-methylenedioxyamphetamine (MDA) has probably been the most consistently abused psychotomimetic phenylethylamine.
Amphetamine and methamphetamine are adrenomimetic at low to moderate dose levels; however, at high dose levels they also become psychotomimetic in man (Liddel and Weil-Malherbe 1953; Connell 1958).
Additionally, it has been found that the addition of an [alpha]-alkyl moiety (up to C-3) (Snyder and Richelson 1970) to methoxyphenylethylamines results in an increase in hallucinogenic activity and, alkyl only substitutions to the aromatic ring tend to result in a gradual loss of central activity which can be related to the increasing size or the alkyl group (Marsh and Herring 1950; Harris and Worley 1957).
Braun et al. (1980b) has determined that a gradual decrease in psychotomimetic activity also occurs with the increasing size of a N-alkyl substituent.
Braun also noted that upon N,N-dialkyl substitution an abrupt and significant loss of hallucinogenic activity occurs, whereas N-hydroxy substitution maintains activity.
The bases of structure-activity relationships as determined by aromatic ring substitutions are not obvious.
For instance, mescaline has relatively prominent psychotomimetic properties but 3,4-dimethoxyphenylethylamine (3,4-dimethoxydopamine) is not considered to be psychotogenic, and the hallucinogenic potency of 3,4-dimethoxyamphetamine is less than that of mescaline (Hollister and Friedhoff 1966).
On the other hand, the hallucinogenic potency of 3,4-methylenedioxyamphetamine is approximately three times that of mescaline (Braun et al. 1980b). Also, tyramine (4-hydroxyphenylethylamine) is devoid of hallucinogenic activity, but 4-methoxy-tyramine is weakly hallucinogenic (Smythies et al. 1969).
However, 2-methoxymethamphetamine has no known hallucinogenic activity (Usdin and Efron 1972), and the 4-methoxyphenyl-[alpha]-methylethylamine (4-methoxyamphetamine) has five limes the psychotropic activity of mescaline (Shulgin 1970).
To complicate the situation further, one work reported the synthesis of 4-substituted methamphetamine derivatives using both ring activating and ring deactivating substituents of quite different atomic volumes, and found hallucinogenic activity present for all derivatives. The compounds in question are 4-bromo-, 4-amino-, 4-chloro-, 4-nitro-, 4-iodo-, and 4-hydroxymethamphetamine (Knoll et al. 1966).
It is a little surprising that substituents of such radically different atomic volumes and electronegativities would all give 4-substituted- phenylisopropylamine derivatives having psychotropic activity.
In contrast, another study of hallucinogenic activity as a function of aromatic ring substitution, found the compound 2,5-dimethoxy-4-methylamphetamine to be some eighty times more potent than mescaline but upon going to the 4-ethyl derivative, quite a trivial change, nearly all hallucinogenic activity was supposedly lost (Shulgin 1969).
Despite these seeming inconsistencies, many of the necessary structural requirements for producing hallucinogenic phenylethylamine can be understood by noting the common structural features of these psychotogens.
The structure activity relationships noted above can be found in a single source review article by Shulgin (1970).
The following phenylalkylamines are listed under Schedule I of the CFR as hallucinogens:
1. 4-bromo-2,5-dimethoxyamphetamine (DOB)
2. 2,5-dimethoxyamphetamine (DMA)
3. 4-methoxyamphetamine (PMA)
4. 5-methoxy-3,4-methylenedioxyamphetamine (MMDA)
5. 4-methyl-2,5-dimethoxyamphetamine (DOM, STP)
6. 3,4-methylenedioxyamphetamine (MDA)
7. 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)
8. 3,4,5-trimethoxyamphetamine (TMA)
9. 2-(3,4,5-trimethoxyphenyl)ethylamine (mescaline)
The majority of the hallucinogenic phenylethylamines which are presently controlled under U. S. law were first encountered in a relatively short period of time in the latter part of 1960.
Since that time the emergence of new CsA's Of psychotogenic phenylethylamines has continued but at a much reduced pace. Starting in 1972, several samples of MDMA were analyzed by DEA laboratories.
Apparently MDMA was readily accepted by the user and abuse has continued to increase. Presently in the U. S. and Canada there are at least four other CsA's of psychotogenic phenylethylamines in the illicit market.
These are N-hydroxy-3,4-methylenedioxyamphetamine (N-hydroxy MDA), N-ethyl MDA (EVE, MDEA), 4-ethoxy-2,5-dimethoxyamphetamine (MEM) (Avdovich et al. 1987), and 4-bromo-2,5-dimethoxyphenylethylamine (DBMPEA) (Sapienza, E personal communication; Allen, A. personal communication).
Upon placing MDMA under legal controls, the N-ethyl homolog of MDA (EVE) was immediately introduced as a replacement for MDMA.
However, it seems that EVE has not been well accepted by the user, apparently because EVE has a lower potency than MDMA; therefore requiring a larger dose to produce psychotropic effects and often resulting in making the user ill (Jordan 1986).
Assuming the ready availability of the appropriate chemical precursors, and assuming a lack of concern for the legal provisions enacted by governments for the purpose of controlling CsA's, choices for CsA's of ring substituted phenylethylamine psychotogens are numerous.
Previously cited literature provides many such CsA possibilities with at least ten aromatic ring substituted amphetamines having potencies greater than mescaline.
Other CsA's can be obtained from by modification of the [alpha]-alkyl side chain to either C-2 or C-3 alkyls, and mono-substitution or the nitrogen with either hydroxy or short chain alkyl.
These modifications result in a total Of 160 possible CsA's based only upon the ring substitutions of the aforementioned compounds.
Additionally, tile ring substituted phenylisopropylamines which are presently controlled substances, can be modified in the same manner, and after excluding controlled substances and N-hydroxy MDA, there are 118 more possible derivatives, giving a total of 278 possible new CsA's.
Each time a new ring substitution is introduced, such as MEM, then this number is increased by 16.
If the U. S. CsA amendment is a consideration, then psychotomimetic phenylethylamines could be created from compounds which are structurally related to dopamine, adrenaline (N-methyl-3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine), and norepinephrine (3,4-dihydroxyphenyl-[beta]-hydroxyethylamine).
A case in point is the compound macromerine, N,N-dimethyl-3,4-dimethoxyphenyl-[beta]-hydroxyethylamine, a known psychotogen (Hodgkins et al. 1967).
Some other compounds which could be used as CsA models are synephrine (N-methyl-4,[beta]-dihydroxyphenylethylamine), phentermine ([alpha],-[alpha]-dimethylphenylethylamine), 4-chlorophentermine, mephentermine (N,[alpha],[alpha]-trimethylphenylethylamine), phenelzine (phenylethylhydrazine), and tranylcypromine (2-phenylcyclopropylamine). Structural modifications of these compounds could provide quite a few additional CsA's.
Because of the sheer size of the task, no attempt was made to determine the total number of possible CsA's that could be derived by using these compounds as models.
However, the magnitude of the possibilities become evident when one calculates tile possible CsA's which, could be obtained using just dopamine as the model compound, as is demonstrated in the following paragraph.
The total number of possible CsA's were limited by the following considerations:
1. ring substitution at C-3,4 is dimethoxy
2. ring substitution to sites C-2,5,6 were limited to combinations of CH3-, Br-, Cl-, and CH30-,
3. substitution on the amine nitrogen and the alpha carbon were limited to the following:
a. of the three ring sites available for substitution, no more than two were allowed for any given structure
b. single substitution on the ring at C-2 to give 2,3,4 tri-substituted derivatives was disallowed
c. mixed halide structures were excluded
d. ring substitutions which would result in any derivative which is presently a controlled substance were disallowed.
Given these considerations there are 47 structures which can be drawn. Each one of these can then exist as 16 derivatives obtained by substitution as shown above at the alpha carbon and nitrogen.
The multiplication product of these two values provides the total number of possible hallucinogenic CsA's (752) which, one could argue, are structurally related to dopamine.
Research targeted at the determination of structure-psychotropic activity relationships has waned in recent years. Perhaps in future years it will be the clandestine chemist who will fill in the blanks.
Phencyclidine
The synthesis of phencyclidine (PCP) was first reported in 1958 (Chen 1958) and patent rights were granted to Parke, Davis & Co. in 1960 and 1963 for medical use as an anesthetic (Parke, Davis & Co. 1960; 1963).
PCP first came to the attention of DEA, then the Bureau of Narcotics and Dangerous Drugs, as a drug of abuse in the latter part of the 1960's.
pharmacologicaly, PCP has been described as a pseudo hallucinogen which has many of the characteristics of a depressant drug (McGlothlin 1971).
Without question, PCP deserves a special niche in any discussion of drugs of abuse if for no other reason than the notoriously bizarre effects it has been known to have upon some of the abusing population (Peterson and Stillman 1978).
The now so very familiar synthesis using 1-(1-piperidyl)cyclo-hexyl carbonitrile and phenyl Grignard reagent was published by Maddox et al. in 1965 and, either fortunately or unfortunately depending upon one's point of view, the accompanying pharmacological data was useless as it could not be correlated to the compounds synthesized (Maddox et al. 1965).
However, pertinent literature is not hard to find as both the original U. S. patent (Godefroi et al. 1963) and later studies have provided a pharmacological basis for the production of CsA's of PCP (Kalir and Pelah 1967; Kalir et al. 1969).
It does not appear to be possible for one to generate a CsA model structure that will not fail under the CsA amendment provision which stipulates that the term controlled substance analogue means a substance-the chemical structure of which is substantially similar to the chemical structure of, in this case, PCP.
This is the result of the fact that a one carbon separation between an aryl system and the amine nitrogen, and the fact that the central carbon between these moieties is in a ring system appear to be principal requirements for PCP-like pharmacological activity. Other activity structure relationships are:
1. substituents which decrease lipophilic character generally decrease potency
2. aryl substitution with 2-thienyl generally increases potency
3. substitutions onto the aryl system decreases potency
4. to maintain potency N,N-dialkyl substitutions should be either piperidino or pyrrolidino ring systems
5. N-ethyl is the most potent N-alkyl monosubstitution and potency falls off rapidly with either an increase or decrease in the alkyl chain size
6. substitution on the beta carbon of either the cycloalkyl or the cycloalkylamino rings will most likely be synthetically difficult due to steric considerations.
Because of factors noted above, there appears to be a relatively small probability of a PCP CsA appearing in the illicit marketplace that will not fall under the purview of the U. S. CsA amendment.
However, it is also the case that under U. S. law there is a reporting requirement placed upon the purveyors of piperidine.
Since the implementation of the piperidine reporting requirement it has become much more difficult for the clandestine chemist to safely acquire this chemical precursor of PCP.
Therefore, a market force has been introduced that will almost certainly result in the production of PCP CsA's which will not contain a simple piperidino moiety. This thought, taken with the previously discussed activity-structure relationships, allows one to suggest the representative of future CsA's of PCP.
Of these 50 compounds, two have already been placedin the CFR Schedule I: N,N-(1-phenylcyclohexyl)-ethylamine and N-(1-phenylcyclohexyl)-pyrrolidine.
Sedatives-Depressants
Depressants include such diverse chemical entities as methaqualone, 5,5-disubstituted barbituric acids, glutethimide and methyprylon, benzodiazepines, chlorhexadol, chloral hydrate, paraldehyde, meprobamate, and ethyl alcohol to name a few.
Historically in the U. S., the abuse of depressants, alcohol aside, has been in major part confined to the barbiturates, methaqualone, and the benzodiazepines.
Barbiturate abuse peaked in the mid 1970's and has since become near nonexistent, in part no doubt, to the well deserved bad press that the barbiturates garnered.
The abuse of methaqualone peaked around 1980 and has also declined steadily since that time. However, much counterfeit lude is still being sold, but instead of containing methaqualone, the tablets now often contain diazepam.
Diazepam has become the most prevalent depressant drug of abuse and its use is apparently continuing to rise. It is somewhat peculiar that of the many benzodiazepines known and readily available in the legal commercial market, diazepam is by far the most extensively abused.
The factors controlling this apparent user preference for diazepam is certainly related, in part, to simple product recognition; however, it is my perception that the dominant factor is the ease with which the drug can be diverted from the legitimate market.
In 1985 the legitimate diazepam market consisted of 5 billion tablets (Franzosa 1985) and since that time generic diazepam tablet production has increased along with even greater product availability for diversion into the illicit market (Franzosa, E. personal communication).
A typical benzodiazepine synthesis is not be considered difficult and a methaqualone synthesis is quite straightforward (Grimmel et al. 1946).
Further, there is a great abundance of literature from which the clandestine chemist can draw in deciding upon a CsA based upon either the benzodiazepines or methaqualone itself.
However, with the very notable exception of methaqualone, the clandestine syntheses of depressant drugs in the U. S. have been extremely rare (Franzosa, E. personal communication).
It is not likely that a clandestinely synthesized benzodiazepine CsA will be encountered as long as the huge, easily diverted legitimate supplies are at hand.
The use of methaqualone is in decline, but it will be with us as an abused substance for still some time. Given the very large numbers associated with the clandestine synthesis of methaqualone, it is perhaps surprising that only two CsA's of methaqualone, have been analyzed at this laboratory.
Again, past history would suggest a high probability for the appearance of new CsA of methaqualone in the future. A CsA of methaqualone will by necessity have the 3-aryl-quinazoline structure, and as a result will fall under the CsA amendment.
One would shell predict that the driving force behind any future clandestine synthesis of a methaqualone CsA will revolve around attempts to use precursor materials which will not alert law enforcement lo the existence of the clandestine laboratory.
A literature review for CsA candidates will quickly surface several possibilities (Boissier and Piccard 1960; Camillo and David 1960; Jackman et al. 1960; Petersen et al. 1963; Boehringer Sohn 1968a,b; Sumitomo Chemical Company 1968; Hurmer and Vernin 1968; Joshi and Singh 1973; 1974).
One of the most intriguing methaqualone CsA's from the perspective of a clandestine chemist would have to be the halo- and thio- derivatives described by Joshi et al. (1975).
Two of the compounds from this work possess depressant activity greater than methaqualone and would be particularly well suited to clandestine synthesis. (continued on page 3)
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