54-04-6

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

Precautionary Statement Codes:

P264, P270, P301+P317, P330, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)

Usage

Uses

Used in Psychedelic Alkaloids:
3,4,5-TRIMETHOXYPHENETHYLAMINE, HYDROCHLORIDE is used as a psychedelic alkaloid for recreational purposes. It is known for inducing hallucinogenic effects and altering perceptions, thoughts, and emotions.
Used in Religious Ceremonies:
In some cultures, 3,4,5-TRIMETHOXYPHENETHYLAMINE, HYDROCHLORIDE is used as a hallucinogenic substance in religious ceremonies for spiritual purposes. It is believed to facilitate a deeper connection with the divine and enhance spiritual experiences.
Used in Scientific Research:
3,4,5-TRIMETHOXYPHENETHYLAMINE, HYDROCHLORIDE is also used in scientific research to study the effects of psychedelic substances on the human brain and their potential therapeutic applications. Researchers are exploring its potential in treating various mental health disorders, such as depression, anxiety, and post-traumatic stress disorder (PTSD).

Hazard

Highly toxic by ingestion.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion route. An experimental teratogen. Other experimental reproductive effects. Human systemic effects by intramuscular route: euphoria and hallucinations, dstorted perceptions. A psychotoimetic agent (a drug of abuse). When heated to decomposition it emits toxic fumes of NOx.

Environmental Fate

The primary exposure pathway is oral via ingestion of the chemical powder or salt or via ingestion of peyote ‘ buttons.’ These buttons are the round, fleshy tops of the cactus that are sliced and dried. Multiple buttons of peyote are typically ingested due to the relatively small content (i.e., 40–50 mg) of individual peyote buttons.

Toxicity evaluation

The exact mechanism of mescaline has not been clearly defined. The central nervous system effects of mescaline appear to involve stimulation of both serotonin and dopamine receptors. In experimental studies, these effects can be blocked by either serotonin antagonists such as methysergide or dopamine antagonists such as haloperidol. Mescaline is structurally related to the amphetamines and cathine and cathinone, which are found in the plant Catha edulis. Mescaline is a ring-substituted phenethylamine. Sympathomimetic effects can occur and are thought to be centrally mediated. High doses of peyote/mescaline can produce more pronounced sympathomimetic effects such as tachycardia and hypertension. Hallucinations may be associated with homicidal, suicidal, or psychotic behaviors. There have been no reported deaths due to the physiological effects of peyote/mescaline. Traumatic deaths have occurred secondary to hallucinations. Mescaline does not appear to inhibit monoamine oxidase.

InChI:InChI=1/C11H17NO3/c1-5-12-8-6-9(13-2)11(15-4)10(7-8)14-3/h6-7,12H,5H2,1-4H3

Upstream product

• 39053-78-6 3,4,5-trimethoxyphenylacetyl chloride 
• 42973-55-7 4-hydroxy-3,5-dimethoxyphenylacetonitrile 
• 40174-10-5 2-(3,4,5-trimethoxyphenyl)ethyl methanesulfonate 
• 1136-86-3 methyl (3,4,5-trimethoxyphenyl) ketone 
• 910866-99-8 5-(2-azidoethyl)-1,2,3-trimethoxybenzene 
• 37785-48-1 2-(3,4,5-trimethoxyphenyl)ethanol 
• 1436392-06-1 benzyl 3,4,5-trimethoxyphenethylcarbamate 
• 832-92-8 mescaline hydrochloride 
• 18066-77-8 N-[2-(3,4,5-trimethoxyphenyl)ethyl]phthalimide 
• 39667-14-6 2,6-dimethoxy-4-<(N,N-dimethylamino)methyl>phenol 
• 91-10-1 1,3-dimethoxy-2-hydroxy-benzene 
• 20329-98-0 (E)-3,4,5-trimethoxy-cinnamic acid 
• 25173-72-2 3-(3,4,5-trimethoxyphenyl)propanoic acid 
• 5320-31-0 3,4,5-trimethoxyphenylacetaldehyde 

Downstream Products

• 80548-66-9 N-(3,4,5-trimethoxy-phenethyl)-butyramide 
• 642-30-8 6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline 
• 124137-77-5 (3-ethyl-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinolin-2-yl)-acetic acid-(3,4,5-trimethoxy-phenethylamide) 
• 4593-89-9 N-acetylmescaline 
• 5990-01-2 N-(3,4,5-trimethoxy-phenethyl)-benzamide 
• 62028-41-5 N-(3,4,5-trimethoxy-phenethyl)-propionamide 
• 6308-78-7 trimethyl-(3,4,5-trimethoxy-phenethyl)-ammonium; iodide 
• 35174-89-1 (4-methoxy-phenyl)-acetic acid-(3,4,5-trimethoxy-phenethylamide) 
• 59801-49-9 4-(3,4,5-trimethoxy-phenethyl)-thiomorpholine 1,1-dioxide 
• 66265-87-0 1-(4-Hydroxy-3-methylsulfanyl-phenyl)-2-[2-(3,4,5-trimethoxy-phenyl)-ethylamino]-ethanone 
• 84752-45-4 ethyl N-(3,4,5-trimethoxyphenethyl)-2,2-dimethylmalonamate 
• 84752-38-5 N-(3,4,5-trimethoxyphenethyl)-3,3-(ethylenedioxy)-5-hydroxy-2,2-dimethylpentanamide 
• 79831-93-9 4,5-dimethoxy-2-nitro-N-(3,4,5-trimethoxyphenethyl)phenylacetamide 
• 79831-92-8 5-benzyloxy-4-methoxy-2-nitro-N-(3,4,5-trimethoxyphenethyl)phenylacetamide 

Relevant academic research and scientific papers

Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.

Structure–activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure–activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 μM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

WOBE437 ((2E,4E)-N-(3,4-dimethoxyphenethyl)dodeca-2,4-dienamide, 1) is a natural product-derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 (1). At the same time, a number of WOBE437 variants exhibited potencies in the sub-100 nM range, with high selectivity over inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1. Interestingly, profound activity differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug-like properties.

Design, synthesis and evaluation of thiourea derivatives as antimicrobial and antiviral agents

Background: The development of drug-resistant by bacteria appears rapidly and thus making the effectiveness of antibiotics severely limited. Methods: A series of thiourea derivatives was synthesized, characterized and evaluated for their in vitro antibacterial, antifungal and antiviral activities. Results: Structures of the newly synthesized compounds were confirmed by elemental and spectral analysis. The biological results showed that some of the target compounds displayed comparable antimicrobial and antiviral activities with reference drugs. Structure-activity relationship studies revealed that the ortho-chloro or fluoro substituted phenyl at Ar1 and substituted pyridinyl at Ar2 positions of the thiourea nucleus are essential for their in vitro antimicrobial and anti-HIV activity. In particular, compounds 8 and 10 showed better activity against the tested bacteria, fungi and viral strains than other synthesized PET derivatives reported in the present study. Conclusion: These results provide an encouraging lead that could be used for the development of new potent antiviral and antimicrobial agents.

Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.

Synthesis and carbonic anhydrase inhibitory properties of sulfamides structurally related to dopamine

A series of novel sulfamides incorporating the dopamine scaffold were synthesized. Reaction of amines and tert-butyl-alcohol/benzyl alcohol in the presence of chlorosulfonyl isocyanate (CSI) afforded sulfamoyl carbamates, which were converted to the title compounds by treatment with trifluoroacetic acid or by palladium-catalyzed hydrogenolysis. Inhibition of six α-carbonic anhydrases (CAs, EC 4.2.1.1), that is, CA I, CA II, CA VA, CA IX, CA XII and CA XIV, and two β-CAs from Candida glabrata (CgCA) and Mycobacterium tuberculosis (Rv3588) with these sulfamides was investigated. All CA isozymes were inhibited in the low micromolar to nanomolar range by the dopamine sulfamide analogues. Kis were in the range of 0.061-1.822 μM for CA I, 1.47-2.94 nM for CA II, 2.25-3.34 μM for CA VA, 0.041-0.37 μM for CA IX, 0.021-1.52 μM for CA XII, 0.007-0.219 μM for CA XIV, 0.35-5.31 μM for CgCA and 0.465-4.29 μM for Rv3588. The synthesized sulfamides may lead to inhibitors targeting medicinally relevant CA isoforms with potential applications as antiepileptic, antiobesity antitumor agents or anti-infective.

Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D 1 receptor

A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D 1 and D2) and serotonin (5-HT1A and 5-HT 2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D1 receptor, as well as high selectivity for the D1 receptor over the D2, 5-HT 1A, and 5-HT2A receptors. Among these, compound 19c exhibited a promising D1 receptor binding affinity (Ki = 2.53 nM) and remarkable selectivity versus D2R (inhibition = 81.87%), 5-HT1AR (inhibition = 61.70%), and 5-HT2AR (inhibition = 24.96%). Compared with l-(S)-stepholidine (l-SPD) (D1 Ki = 6.23 nM, D2 Ki = 56.17 nM), compound 19c showed better binding affinity for the D1 receptor (2.5-fold higher) and excellent D2/D1 selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D1 receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D1 receptor. These results are in accord with molecular docking studies.

Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor

Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. In searching for up-regulators effective for both LDLR and InsR expression, the structure-activity relationship (SAR) analysis for BBR analogues was done. Fourteen BBR analogues were designed, synthesized and biologically evaluated. SAR analysis revealed that appropriate modifications on the phenyl ring A or D of BBR might retain the up-regulatory activities on the expression of both LDLR and InsR. Among these compounds, compound 13a bearing 9-methoxy and 10-hydroxyl on the ring D showed promising activities on either LDLR or InsR gene expression. The 10-hydroxyl of 13a could be an arm to connect proper chemical groups for optimizing drug-bioavailability in vivo. Thus, 13a could be considered to be a parent compound to make pro-drugs for either blood lipids or glucose.

A very mild access to 3,4-dihydroisoquinolines using triphenyl phosphite-bromine-mediated bischler-napieralski-type cyclization

Substituted β-phenylethylamides undergo smooth intramolecular cyclization to 3,4-dihydroisoquinolines in good to excellent yields when treated with bromotriphenoxyphosphonium bromide at -60°C in dichloromethane in the presence of triethylamine. The reaction proceeds under the mildest conditions ever reported for Bischler-Napieralski-type cyclizations. When chlorotriphenoxyphosphonium choride is used, low yields are obtained instead. Georg Thieme Verlag Stuttgart.

Regioselective Heck reaction of N-vinylphthalimide: A general strategy for the synthesis of (E)-N-styrylphthalimides and phenethylamines

The arylation of N-vinylphthalimide takes place at the β-position with aryl iodides, bromides and chlorides using palladium acetate [Pd(OAc) 2] or phenone oxime-derived palladacycles as catalysts under phosphine-free conditions. The reaction is succesfully carried out in organic solvents, such as DMF, in the presence of an organic base, such as dicyclohexylmethylamine, and with TBAB as additive at 120°C under conventional or microwave heating. (E)-N-Styrylphthalimides are mainly obtained using a rather low palladium loading (0.05-1 mol%). Similar catalytic efficiency is observed using a Kaiser oxime resin-derived palladacycle, which allows reuse of the polymeric complex for three cycles. The high regioselectivity observed supports that these palladacycles work as a source of Pd(0)spec ies operating mainly through a neutral mechanism. The syntheses of 2-thienylphenethylamine and mescaline have been performed by subsequent hydrogenation with Wilkinson's catalyst and hydrazinolysis.