Search

Background: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models., Methods: In the present study, the head twitch response (HTR), a 5-HT 2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine)., Results: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2., Conclusions: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor.

A directed C-H bond activation approach to the synthesis of indans, tetralins, dihydrofurans, dihydroindoles, and other polycyclic aromatic compounds is presented. Cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using (PPh3)3RhCl (Wilkinson's catalyst). The cyclization of a range of aromatic ketimines and aldimines provides bi- and tricyclic ring systems with good regioselectivity. Different ring sizes and substitution patterns can be accessed through the coupling of monosubstituted, 1,1- or 1,2-disubstituted, and trisubstituted alkenes bearing both electron-rich and electron-deficient functionality.

[reaction: see text] A tetrahydrobis(benzofuran) mescaline analogue has been prepared in six steps and 38% overall yield from (4'-O-methyl)methyl gallate. The key step in this synthesis is a tandem cyclization reaction via directed C[bond]H activation followed by olefin insertion.

Four known compounds have been isolated from the aerial parts of the Brazilian medicinal plant Pariparoba (Pothomorphe umbellata). They were an alkaloid, a flavone, a dihydrocalcone, and a steroid. The chemical structures were established to be N-benzoylmescaline, wogonin, uvangoletin, and beta-sitosterol glucoside using spectral methods. Among these compounds, the main component N-benzoylmescaline showed significant antibacterial activity against Helicobacter pylori.

Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b']difuran-4-yl)-2- aminoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Although 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mumol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

Mescaline (3,4,5-trimethoxyphenylethylamine; MES) and its analogs, anhalinine (ANH) and methylenemescaline trimer (MMT) were investigated, using sciatic-sartorius preparations of the frog and cortical tissue from the rat. The effects of MES and its analogs were examined with respect to muscle twitch, resting membrane potential and nicotinic receptor binding. Mescaline and its analogs (10-100 microM) blocked both directly and neurally evoked twitches but their effects on neurally evoked twitches were greater than those on directly evoked twitches. Mescaline, ANH and MMT decreased amplitude of the miniature endplate and endplate potentials, decreased acetylcholine (ACh) quantal content, hyperpolarized the resting membrane potential and prolonged duration of the action potential. They did not significantly displace the binding of [125I]-alpha-bungarotoxin (alpha-BTX) to nicotinic receptors, at concentrations which blocked neuromuscular transmission. These results suggest that MES and its analogs inhibit cholinergic neuromuscular transmission by blocking release of ACh; they also affect K+ conductance.

"Adam," "Eve," "ecstasy," "China white." Illicit street drugs such as these are called designer drugs because they are designed to elicit certain effects and to bypass legal classification. Unfortunately, use and abuse of such substances can lead to serious medical problems and even death. Drs Sternbach and Varon describe the best-known compounds and discuss clinical characteristics and management of designer drug intoxication.

Use of "designer drugs" has created a new dilemma for physicians. Generally, it is possible to recognize symptoms and signs of intoxication that fit a specific class of substances, such as amphetamine-like effects for the phenylethylamines and opioid effects for the fentanyl analogues. Designer compounds have crossed these boundaries, and toxicology laboratories cannot readily identify them. For now, physicians must rely on clinical presentation and treat accordingly.

Designer drugs, chemically altered compounds derived from federally controlled substances, have become a major cause of addiction and overdose deaths. These drugs include mescaline analogs, synthetic opioids, arylhexylamines, methaqualone derivatives and crack, a new form of cocaine. Sudden changes in mood, weight loss, depression, disturbed sleep patterns, deteriorating school or work performance, marital problems, and loss of interest in friends and social activities may be signs of drug addiction. Life-threatening complications of acute intoxication, such as hyperthermia, seizures, combative and psychotic behavior, and cardiorespiratory collapse, require prompt diagnosis and supportive intervention.

1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

The central effect of mescaline and of its derivative N-[3,4,5- trimethoxyphenylethyl]-aziridine (FAZ) after their stereotaxic administration into the lateral ventricle of the brain was studied in behavioural experiments on rats. The effect of the two substances was tested by a method studying memory elicitation in response to appetitive motivation in a multiple T-maze. The results show that both substances worsened the behaviour in question. The negative effect of mescaline (lengthening of the time of passage through the maze) was manifested both immediately and several weeks after a single dose. FAZ likewise worsened the test reaction, but its effect was less pronounced than that of mescaline.

All possible monothio analogues of the mono-, di-, and triethoxy homologues of mescaline have been synthesized and pharmacologically evaluated in man. Modifications at the ring position para to the ethylamine chain, either with a sulfur atom, a longer alkyl chain, or both, lead to compounds of high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also synthesized and pharmacologically evaluated. The propyl homologues retain high potency, but a butyl group (either with or without a sulfur atom) leads to a decrease in activity. The m-ethyl or m-thio analogues retain some central action but the diethoxy and especially the triethoxy homologues are relatively inactive as psychotomimetic drugs.

Replacement of the 4-methoxy of mescaline with higher alkyl homologues or with bromine led to increased activity at serotonin receptors in a sheep umbilical artery preparation. This activity appears correlated with lipophilicity, as measured by 1-octanol-water partition coefficients, but drops off when the 4-substituent is about five atoms in length. It is suggested that 3,4,5-trisubhe 2,4,5-substitution pattern.

Antibodies with mescaline binding specificity were raised in rabbits by immunization with conjugates of bovine serum albumin with mescaline or its analogue 3,4,5-trimethoxyphenylacetic acid. Immunized rats were given mescaline and their behavior was compared to that of non-immunized controls.

The authors examine folk psychiatry among Native American Church members from an enthnopharmacologic viewpoint. Alcohol and opiate abuse among Indian and non-Indian are presented in case histories proving to be asymptomatic under Indian guidance and through participation in the peyote ritual. The biochemical alkaloids common in the peyote cactus, rather than just the psychoactive substances (mescaline), are purported to be pharmacologically similar to the neuroamine-derived alkaloids found in the brain during alcohol intoxification. Evidence is reviewed that points out possible common features of alcohol and opiate dependence leading to the speculation for a common mode of treatment may reside in plants rich in isoquinoline alkaloids.

The regional distribution of radioactivity was studied in the brain and in other organs of the mouse by light microscopic autoradiography after injection of 3H-2,3,4-trimethoxy-beta-phenylethylamine (2,3,4,-TMPEA), a nonhallucinogenic isomer of mescaline. The distribution patterns were compared with biochemical and autoradiographic results obtained after 3H-mescaline. Although 2,3,4-TMPEA is rapidly deaminated compared to mescaline its distribution pattern in the brain is similar to that of mescaline at 1 h after injection. However, contrary to mescaline the radioactive labeling becomes more and more homogenously distributed in the brain with tiem. The distribution patterns in kidney, pancreas, adrenal, and spinal ganglia were also different from those observed after application of 3H-mescaline.

Structural juxtaposition of the 3,4,5-trimethoxyphenyl group in the same molecule with a piperazine or homopiperazine ring has been realized in a series of mescaline analogues (I-IV) as part of an investigation into the pharmacological properties of the seven-membered perhydro-1,4-diazepines (homopiperazines). The analogous six-membered piperazines were synthesized and tested as reference substances to determine whether the seven-membered ring conveyed special properties. A variety of pharmacological tests of action on the CNS showed that replacement of the amino group in mescaline by the heterocycles significantly alters the biological activity. In particular, both the piperazine and the homopiperazine derivatives displayed sedative activity to about the same extent.

The purpose of this study was to investigate possible similarities in the interoceptive stimuli produced by mescaline and its metabolites. Rats were trained in a 2 lever operant chamber to discriminate between the drugged state (mescaline 25 mg/kg) and the nondrugged state (saline). Following acquisition of discriminative response control the rats were pretreated with either saline, aldehyde dehydrogenase inhibitors or amine oxidase inhibitors and tested stimulus generalization produced by i.p. injections of 3, 4, 5-trimethoxyphenylethanol (TMPE), 3, 4, 5-trimethoxyphenylacetaldehyde (TMPA), N-acetylmescaline, mescaline or saline. The results indicated that both aldehyde dehydrogenase and amine oxidase inhibitors enhanced the effects of mescaline, while TMPE, TMPA and N-acetylmescaline failed to exhibit generalization to the mescaline state, regardless of pretreatment. These findings do not indicate the role of a metabolite in the interoceptive cue produced by mescaline.

The nature of the substituents and their contribution at different ring positions to the overall hallucinogenic activity in a series of phenylalkylamines (amphetamines) are studied by using Fujita-Ban additive model. The calculated activity contributions of substituents and of parent structure, respectively, are then utilized to predict the most potent compound in the series and to remove the uncertainties in the observed activity of some phenylalkylamines. The most potent compound predicted is 2,6-dimethoxy-4-bromophenylisopropylamine.

Attempt is made to correlate the hallucinogenic activity of a series of mescaline analogs with Kier's molecular connectivity index (chi). In order to find a simpler and more meaningful correlation, a little modification is suggested to the first-order valence connectivity index (1 chi upsilon). The modification is found to reveal utterly simple but significant correlations between activity and 1 chi upsilon, which could describe the structural influence on the activity more vividly.

The synthesis of methyl-2-(3,4,5-trimethoxyphenyl)-2-(2-piperidyl) acetate is described. In addition, preliminary pharmacological data comparing the compound with mescaline are given.

Agurell has previously detected (tlc, glc-ms) tyramine, 3-methoxytyramine, and two unknown alkaloids in the Peruvian cactus, Trichocereus peruvianus Br. and R. The presence of mescaline in other similar Trichocereus species prompted us to reinvestigate this species, which is commercially available in the United States. The nonphenolic alkaloid extracts yielded an abundance of crystalline mescaline hydrochloride (0.82% yield) and a trace of 3,4-dimethoxyphenethylamine (tlc-ms). Crystalline tyramine hydrochloride, 3-methoxytyramine hydrochloride, and 3,5 dimethoxy-4-hydroxphenethylamine hydrochloride were isolated from the phenolic alkaloid extracts; the last compound has not been previously crystallized from nature, although it is the immediate biosynthetic precursor of mescaline. Crystalline 2-chloromescaline hydrochloride was isolated drom the nonphenolic extracts; but, as determined by mass-analyzed ion kinetic energy spectrometry, this new compound is an extraction artifact. Both 2-chloromescaline and 2.6-dichloromescaline hydrochlorides were prepared synthetically from mescaline. This cactus species has a mescaline content equal or superior to peyote and should be legally controlled as an item of drug abuse.

The nature of the stereochemistry and aromatic ring substituents and their importance to biological activity for phenethylamine-type hallucinogens is presented. The possibility of a hydrophobic site to bind to the 4-substituent and its likely geometry is described. A brief discussion of the structure-activity relationships for tryptamines such as psilocin and DMT is also given, with comments about the stereochemistry of alpha-methyltryptamines. Evaluation of a series of N(6)-alkyl-nor-LSD derivatives indicated that selected members such as N(6)-ethyl, allyl and propyl were as potent as, if not more potent than LSD, both in a two-lever drug discrimination assay in rats, and in man. N(6)-alkyl groups longer than n-propyl, such as n-butyl or 2-phenethyl, gave compounds that were greatly reduced in activity.

Tactile startle responding by male Sprague-Dawley rats given 60 presentations of air-puff stimuli (37.5 psi) was measured after the intraperitoneal administration of graded doses of hallucinogens and other psychoactive drugs. Among the drugs tested were the indoleamine-derived compounds, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine and psilocin, and the phenylethylamine-derived compounds, mescaline, 2,5-dimethoxy-4-methylamphetamine and a series of active and inactive congeners of 2,5-dimethoxy-4-methylamphetamine. All of the active phenylethylamines increased startle response magnitudes throughout the test session. This pattern of augmented startle suggests that these drugs increase reactivity. However, none of the indoleamine hallucinogens increased startle responding. Of the nonhallucinogenic drugs tested, only apomorphine increased startle responding, while clonidine significantly decreased it, and amphetamine, chlorimipramine, scopolamine and methysergide had no effect. In additional studies with LSD, it was found that LSD increased the response to only the first stimulus when more intense air-puffs were used (50 psi). Furthermore, when the number of stimuli was increased from 60 to 240 (1 hr) so that appreciable habituation was evident in controls, LSD impaired this habituation. Whereas the response magnitudes of the control group decreased by 70% across the session, the responses of LSD-treated rats decreased by only 32%. These results suggest that LSD and phenylethylamine-derived hallucinogens may differ in their effects on tactile startle responding.

The action of alpha-fluorinated mescalins on induction of diapause in the cabbage butterfly, Pieris brassicae, has been studied. The introduction of fluorine into mescalin has no influence on this activity. This result suggests solvolysis of fluorine and in vivo formation of a common ethylimine intermediate. Activity decreases, however, with substitution of the nitrogen.

The hallucinogenic (psychotomimetic) potency of 10 mescaline analogs was examined by molecular connectivity analysis. Potencies could be described by a two-term relating equation, which explained 94% of the variance in activity, on the basis of structural variation, 2,5-Dimethoxy substitution as well as the nature of the 4-position substituent played an important role in determining hallucinogenic potency. With the relating equation, reasonable potency predictions were made for six compounds not included in the initial investigation.