Phenylalkylamine Hallucinogens Research Articles

Qualitative analysis of synthetic opioids, synthetic hallucinogens and LSD in urine using LC-MS/MS

ABSTRACTSynthetic opioids and synthetic hallucinogens continue to expand in the illicit drugs market where they are designed and synthesized to avoid detection in routine drug tests. It is therefore crucial for laboratories to develop analytical methods for the detection of these drugs in urine. A method for the simultaneous analysis of synthetic opioids (including fentanyl, furanyl fentanyl, U-47700 and AH-7921), phenylalkylamine hallucinogens (25C-NBOMe, 25B-NBOMe, 25I-NBOMe, 25H-NBOMe, 25C-NBOH, 25B-NBOH, 25I-NBOH and 25H-NBOH) along with LSD, 2-oxo-3-OH-LSD (Oxo-LSD), psilocin and bufotenine was hence developed. Briefly, urine samples (0.5 mL) underwent enzymatic hydrolysis and matrix clean-up using supported-liquid extraction (SLE) prior to analysis on LC-MS/MS. The SLE extraction recoveries ranged from 62.8% to 97.4% and limits of detection between 0.1–3 ng/ml were achieved. The matrix effects results ranged from 70.6% to 124.9% and there was no carryover up to 100 ng/ml for psilocin and bufotenine and 30 ng/ml for the rest of the analytes. Extracted urine samples were stable for up to three days for Oxo-LSD and seven days for the rest when stored at 4°C. The method was validated to be accurate and precise for each analyte at their individual cut-off points. It was also successfully applied on suspected drug abusers’ urine samples.

Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (“FLY”) and benzodifuran (“DragonFLY”) analogs

In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 μmol/kg) and 2C-B (ED50 = 2.43 μmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 μmol/kg) and 2C-B-DFLY (ED50 = 1.07 μmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 μmol/kg) and 2C-B-FLY (ED50 = 1.79 μmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

The 5-HT2A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT2A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT2A knockout mice, indicating the effect is a consequence of 5-HT2A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1–10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT2A activation and hallucinogenesis.

A novel quantum theoretic QSAR for hallucinogenic tryptamines: a major factor is the orientation of π orbital nodes

For a series of hallucinogenic tryptamines, activity has been shown to depend mainly on the orientation of one of the nodes in the highest occupied π-like orbital, and to a lesser degree on the lipophilicity of the amine nitrogen substituents. This agrees with previous work on phenylalkylamine hallucinogens. At least 74% of the variance in log activity can be explained in terms of the angular variable alone. This conflicts with the common view that interaction of a ligand with a receptor is explicable in classical rather than quantum theoretic terms. The activity of the β-carboline hallucinogen harmaline is also accounted for by this QSAR without further assumptions, however, those of the very potent ergoline hallucinogens, that include an extra double bond conjugated to the aromatic ring system, are not.

Quantum Theoretic QSAR of Benzene Derivatives: Some Enzyme Inhibitors

Our previously developed approach to the development of QSAR equations for benzene derivatives, originally for phenylalkylamine hallucinogens, has been applied to four new systems: sulfonamide inhibitors of the enzymes carbonic anhydrase, thrombin, trypsin, and Clostridium histolyticum collagenase. The novel features involve the energies and nodal orientations of π-like orbitals, and an allowance for the symmetry of the benzene nucleus. The resulting equations give better fits, better predictivity and are more easily interpretable than those resulting from traditional QSAR methods.

Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5- g]isoquinoline

This investigation is based on the premise that conformational restriction of abused phenylalkylamines in a tetrahydroisoquinoline conformation alters their pharmacology in such a manner that their original action is lost and that a new action emerges. TDIQ or 5,6,7,8-tetrahydro-1,3-dioxolo[4,5- g]isoquinoline, is a conformationally constrained phenylalkylamine that serves as a discriminative stimulus in animals. Although TDIQ bears structural resemblance to phenylalkylamine stimulants (e.g., amphetamine), hallucinogens (e.g., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane [DOM]), and designer drugs (e.g., N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane [MDMA], N-methyl-1-(4-methoxyphenyl)-2-aminopropane [PMMA]), the TDIQ stimulus failed to generalize to (+)amphetamine or MDMA. In the present investigation, further evaluations were made of the stimulus nature of TDIQ. Specifically, the stimulus similarities of TDIQ, PMMA, and DOM were examined. In no case was stimulus generalization (substitution) observed. The results confirm that TDIQ produces stimulus effects distinct from those of the abovementioned phenylalkylamines. We also examined the structure–activity relationships of a series of TDIQ analogs, including several that might be viewed as conformationally restricted (CR) analogs of phenylalkylamine hallucinogens, stimulants, and designer drugs. These agents were examined in rats trained to discriminate either DOM (1.0 mg/kg), (+)amphetamine (1.0 mg/kg), MDMA (1.5 mg/kg), or TDIQ (5.0 mg/kg) from saline vehicle. Whereas we have demonstrated that none of these agents retains their respective phenylalkylamine stimulus actions, several of these agents were found to substitute for TDIQ. N-Methylation abolished TDIQ-stimulus action. These results, coupled with previous findings, imply that TDIQ derivatives represent a novel class of phenylalkylamines analogs with unique stimulus properties. Preliminary radioligand binding studies suggest that an α 2-adrenergic mechanism might underlie the stimulus effects produced by TDIQ.

QSAR of benzene derivatives: comparison of classical descriptors, quantum theoretic parameters and flip regression, exemplified by phenylalkylamine hallucinogens.

A physical model of electronic effects in the QSAR of benzene derivatives, together with a regression technique for finding predictive equations, is presented. The model is simple, based on the quantum theoretic description of the benzene molecule, and accounts for the variance in activity of hallucinogenic phenylalkylamines as well as a classical description in terms of electronic (atomic charge, orbital energy), hydrophobic (Hansch pi) and steric (substituent volume) terms. The new model involves the energies of four pi-like near frontier orbitals and the orientations of their nodes. It is less affected by colinearity than the classical approach. This model more than any other illustrates the essential wave mechanical nature of the interaction of a drug with its receptor, as the pi-like orbitals involved are standing waves of probability of finding an electron in a given location in the field of the atomic nuclei, and have no classical counterpart.

Indolealkylamine analogs share 5-HT 2 binding characteristics with phenylalkylamine hallucinogens

Twenty-one indolealkylamines, some of which are known to be psychoactive in man, were examined for their binding interactions with rat brain cortical 5-HT 2 receptors labeled with the antagonist radioligand [ 3H]ketanserin in order to develop structure-activity relationships for binding at these sites. Features investigated included aromatic, α-methyl and terminal amine substituents. 4-Methoxy and 5-methoxy substitution impart a higher affinity than 6- or 7-methoxy substitution; a 7-hydroxyl group essentially abolishes affinity whereas a 7-methyl or 7-bromo group enhances affinity. α-Methylation has little effect on affinity and, in the one case examined, the S(+) isomer of α-methyltryptamine was essentially equipotent with its racemate and twice as potent as its R(−) enentiomer. Terminal amine methylation results in a small but progressive decrease in affinity in the order: primary amine > dimethylamine > diethylamine. Similarities were noted between these structural requirements for binding and those of the phenalkylamines. Selected compounds (5-methoxytryptamine, N,N-dimethyltryptamine, 5-methoxy-N,N-diethyltryptamine and 5-methoxy-N,N-dimethyltryptamine) were further examined by two-site analysis of displacement studies for [ 3H]ketanserin specific binding. Hill co-efficients were significantly less than unity and computer-assisted analysis indicated that a two-site model better fit the data than a one-site model. In displacement studies using the putative agonist radioligand [ 3H]DOB to label 5-HT 2 receptors affinities were 10-100-fold higher than those using [ 3H]ketanserin. These results are also consistent with earlier findings using psychoactive phenalkylamines in competition studies for radiolabelled 5-HT 2 receptors. In summary, the interactions of indolealkylamines and phenalkylamines with 5-HT 2 receptors have many characteristics in common, supporting the hypothesis that 5-HT 2 receptors may mediate the psychoactive properties of indolealkylamines.