Journal of Medicinal Chemistry

Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes

Journal of Medicinal Chemistry May 1, 1982 David E. Nichols, David Harley Lloyd, Andrew J. Hoffman et al. 178 citations

The enantiomers of MDA, PMA, and MDMA, along with their alpha,alpha-dimethylated derivatives, were tested for their ability to release serotonin from rat whole brain synaptosomes. At bath concentrations of 1 and 10 micrometers, the amphetamine isomers potently induced serotonin release, but were inactive at 0.1 micrometers. At 1 micrometer, the (+) isomer of MDMA was more effective than the (-) isomer, and because the (+) isomer is the clinically active form, this suggests that transmitter release may contribute to MDMA's biological activity. The alpha,alpha-dimethyl compounds did not release serotonin even at the highest concentration.

DOI: 10.1021/jm00347a010 MDMA Citation Amphetamine Computer science +2

Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines

Journal of Medicinal Chemistry October 19, 2000 Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka et al. 132 citations

Fluorination of hallucinogenic tryptamines generally preserves their affinity and intrinsic activity at 5-HT2A/2C serotonin receptors but reduces affinity at the 5-HT1A receptor, except for one compound. 4-Fluoro-5-methoxy-DMT (compound 6) showed markedly enhanced 5-HT1A receptor affinity (Ki = 0.23 nM) and functional potency, greater than the standard 5-HT1A agonist 8-OH-DPAT, with an ED50 of 0.17 µmol/kg in a drug discrimination assay. Hallucinogen-like activity was attenuated or abolished for all fluorinated analogues. The findings suggest that while 5-HT2A activation is key for hallucinogenic effects, the 5-HT1A receptor may also play a role with tryptamines.

DOI: 10.1021/jm000339w Serotonin Tryptamines Hallucinogen Partial agonist +5

Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD)

Journal of Medicinal Chemistry September 1, 2002 David E. Nichols, Stewart Frescas, Danuta Marona‐lewicka et al. 89 citations

Lysergic acid amides containing a rigid dimethylazetidine ring—a constrained version of diethylamine—were synthesized and tested for hallucinogenic activity. The (S,S)-(+)-2,4-dimethylazetidine lysergamide showed slightly greater LSD-like behavioral effects in rats than LSD itself and had the highest affinity and functional potency at the serotonin 5-HT(2A) receptor, the presumed target for hallucinogens. Its receptor profile across a panel of screens most closely matched that of LSD. In contrast, the cis- and (R,R)-trans-dimethylazetidine lysergamides were less potent. These results suggest that the N,N-diethyl groups of LSD bind optimally in a conformation different from that seen in the solid state. Incorporating isomeric dialkylazetidines into other molecules may help model active conformations of dialkylamines and dialkylamides.

DOI: 10.1021/jm020153s Lysergic acid diethylamide Hallucinogen Moiety Stereochemistry +5

Dihydrobenzofuran Analogues of Hallucinogens. 4. Mescaline Derivatives

Journal of Medicinal Chemistry September 1, 1997 Aaron Monte, Steve R. Waldman, Danuta Marona‐lewicka et al. 89 citations

Conformationally restricted bioisosteres of mescaline's methoxy groups—dihydrobenzofuran (8) and tetrahydrobenzodifuran (9)—were synthesized and tested against mescaline (1) in drug discrimination assays in rats trained to discriminate LSD from saline. Neither 8 nor 9 substituted for LSD: only 50% of rats given 8 and 29% given 9 selected the drug lever, whereas mescaline fully substituted (ED50 = 33.5 mumol/kg). All compounds showed micromolar affinity for 5-HT1A and 5-HT2A receptors in rat brain homogenate, but rank order of affinities at 5-HT2A sites reversed their behavioral potency. At 5-HT2A receptors, 8 and 9 were less efficacious (61% and 45% of maximal response), while all compounds matched serotonin's efficacy at 5-HT2C receptors.

DOI: 10.1021/jm970219x Mescaline Serotonin Lysergic acid diethylamide Pharmacology +12

Nonneurotoxic tetralin and indan analogs of 3,4-(methylenedioxy)amphetamine (MDA)

Journal of Medicinal Chemistry February 1, 1990 David E. Nichols, William K. Brewster, Michael P. Johnson et al. 83 citations

Four cyclic analogues of the psychoactive compound MDA were tested in rats trained to discriminate either LSD or MDMA from saline. None of the methylenedioxy compounds caused LSD-like effects, but two of them (3a and 3b) fully substituted for MDMA, indicating similar acute behavioral effects. However, unlike MDA, neither 3a nor 3b reduced serotonin or its metabolite levels in the cortex or hippocampus, nor did they decrease serotonin transporter binding sites after a single 40 mg/kg dose. These results suggest that 3a and 3b share MDMA-like acute behavioral properties but lack the serotonin neurotoxicity associated with MDA.

DOI: 10.1021/jm00164a037 Citation Icon Computer science Information retrieval +1

Structure-activity studies on hallucinogenic amphetamines using molecular connectivity

Journal of Medicinal Chemistry December 1, 1977 Lemont B. Kier, Lowell H. Hall 64 citations

A series of ring-substituted hallucinogenic amphetamines was analyzed using molecular connectivity, and a correlating equation was found between potency and connectivity terms. The equation allows interpretation of structure-activity relationships (SAR) and can predict potency for amphetamines not in the original list, as well as for mescalines and tryptamines.

DOI: 10.1021/jm00222a019 Icon Computer science Citation database Information retrieval +1

Synthesis and serotonin receptor affinities of a series of enantiomers of .alpha.-methyltryptamines: evidence for the binding conformation of tryptamines at serotonin 5-HT1B receptors

Journal of Medicinal Chemistry July 1, 1988 David Nichols, D. H. Lloyd, Michael P. Johnson et al. 46 citations

A new method produces pure mirror-image forms of alpha-methyltryptamines (AMTs) from substituted indoles. The key step uses reductive amination with pure enantiomers of alpha-methylbenzylamine, followed by chromatographic separation and catalytic N-debenzylation. Optical purity was confirmed by chiral HPLC. Affinities of the AMT enantiomers were measured at 5-HT2 and 5-HT1B serotonin receptor subtypes in rat frontal cortex homogenates. Enantioselectivity depended on aromatic substituents: for 5-hydroxy or 5-methoxy, the S enantiomer had higher or equal affinity compared to the R enantiomer. For 4-oxygenated AMTs, this selectivity reversed, and 4-hydroxy or 4-methoxy did not improve affinity over unsubstituted compounds. The results suggest a binding conformation where the ethylamine side chain is trans and perpendicular to the indole ring plane.

DOI: 10.1021/jm00402a026 Serotonin Enantiomer Tryptamines Stereochemistry +5

Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives

Journal of Medicinal Chemistry September 1, 1985 Andrew J. Hoffman, David E. Nichols 44 citations

A series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was synthesized and tested in rats trained to discriminate LSD from saline. The N(6)-ethyl and -allyl derivatives were 2–3 times more potent than LSD itself, the N(6)-propyl was equally potent, the isopropyl derivative was half as active, and the n-butyl compound was 10 times less potent. No substitution occurred for norlysergic acid N,N-diethylamide or the N(6)-2-phenethyl derivative. These structure-activity relationships resemble those of certain serotonin and dopamine agonists.

DOI: 10.1021/jm00147a022 Lysergic acid diethylamide Alkyl Stimulus control Discriminative model +1

Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines

Journal of Medicinal Chemistry December 1, 1975 Alexander T. Shulgin, Donald C. Dyer 37 citations

A series of chemically related compounds, 4-alkyl-2,5-dimethoxyphenylisopropylamines with alkyl groups ranging from hydrogen to five-carbon straight chains and a branched four-carbon chain, was synthesized and tested for their ability to mimic serotonin in a sheep umbilical tissue preparation. Among the straight-chain variants, the compound with a three-carbon alkyl group was the most potent, matching its known mind-altering effects in humans.

DOI: 10.1021/jm00246a006 Mescaline Psychotomimetic Homologous series Alkyl +2

Serotonin Receptor Binding Affinities of Several Hallucinogenic Phenylalkylamine and N,N-Dimethyltryptamine Analogues

Journal of Medicinal Chemistry January 1, 1978 35 citations

Several hallucinogenic compounds related to phenylalkylamine and N,N-dimethyltryptamine bind to serotonin (5-HT) receptors in rat stomach tissue. The most behaviorally potent analogues tested—DOB, DOM, and 5-methoxy-N,N-dimethyltryptamine—showed high binding affinities, with pA2 values of 7.35, 7.12, and 7.08, respectively.

DOI: 10.1021/jm00206a022 Full text

Studies on several 7-substituted N,N-dimethyltryptamines

Journal of Medicinal Chemistry November 1, 1980 R. A. Glennon, E. Schubert, John M. Jacyno et al. 33 citations

Several 7-substituted derivatives of N,N-dimethyltryptamine (DMT) were synthesized and tested. 7-Me- and 5-OMe-7-Me-DMT showed higher serotonin receptor affinity (pA2) than DMT itself, while 5,7-(OMe)2-DMT showed lower affinity. All three produced behavioral effects in rats similar to the hallucinogen 5-OMe-DMT. 7-ET- and 7-Br-DMT had higher receptor affinity than DMT but did not produce hallucinogen-like behavioral effects. 6-Me-DMT and its 5-OMe derivative did not interact competitively with serotonin receptors and were inactive in the behavioral assay.

DOI: 10.1021/jm00185a014 Stereochemistry

1-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines as mGluR2 Positive Allosteric Modulators for the Treatment of Psychosis

Journal of Medicinal Chemistry March 2, 2011 Lei Zhang, Michael A. Brodney, John Candler et al. 32 citations

A new class of compounds, 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, acts as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2). Structure-activity relationship studies produced potent and selective mGluR2 PAMs with favorable pharmacokinetic properties. The lead compound (+)-17e dose-dependently reduced methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, suggesting potential for treating psychosis.

DOI: 10.1021/jm101414h Mescaline Allosteric regulation Methamphetamine Pharmacology +3

Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes

Journal of Medicinal Chemistry March 1, 1995 Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al. 25 citations

Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.

DOI: 10.1021/jm00006a015 Lysergic acid diethylamide Stereochemistry Stereoselectivity Carboxamide +3

C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor

Journal of Medicinal Chemistry June 21, 2006 Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al. 24 citations

A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.

DOI: 10.1021/jm060272y Mescaline Potency Stereochemistry Homology modeling +8

Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogs

Journal of Medicinal Chemistry February 1, 1977 David E. Nichols, Donald C. Dyer 23 citations

Replacing the 4-methoxy group of mescaline with larger alkyl groups or bromine increases activity at serotonin receptors in a sheep umbilical artery preparation. This increase correlates with lipophilicity, measured by 1-octanol-water partition coefficients, but activity declines when the 4-substituent reaches about five atoms in length. The findings suggest that a 3,4,5-trisubstituted pattern may be more effective than a 2,4,5-substitution pattern for receptor activity.

DOI: 10.1021/jm00212a022 Mescaline Lipophilicity Stereochemistry Serotonin agonist +2

Sulfur analogues of psychotomimetic agents. Monothio analogs of mescaline and isomescaline

Journal of Medicinal Chemistry November 1, 1981 Peyton Jacob, Alexander T. Shulgin 20 citations

Two sulfur-containing analogues of mescaline, 3-thiomescaline and 4-thiomescaline, were synthesized and found to be psychotomimetic in humans, with 4-thiomescaline being 12 times more potent and 3-thiomescaline 6 times more potent than mescaline itself. Three additional analogues of isomescaline were also synthesized but were not psychotomimetic. All five compounds were broken down by bovine plasma monoamine oxidase in the lab, but the rate of this enzymatic degradation did not correlate with their potency as hallucinogens in people.

DOI: 10.1021/jm00143a017 Mescaline Chemistry Psychotomimetic Pharmacology +1

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

Journal of Medicinal Chemistry November 20, 2023 Kaveh Matinkhoo, Lisa Yu, David Press et al. 18 citations

Psilocybin's therapeutic benefits for depression and anxiety are limited by the long duration of its psychedelic effects, driven by sustained exposure to its active metabolite psilocin. To address this, researchers synthesized and screened 28 new chemical entities, introducing various cleavable groups at the 4-hydroxy position of the indole core to alter metabolic processing. Several novel prodrugs showed altered pharmacokinetic profiles and reduced pharmacological exposure compared to psilocybin, suggesting they could maintain long-term therapeutic benefits while shortening the psychedelic experience.

DOI: 10.1021/acs.jmedchem.3c01225 Psilocybin Anxiety Prodrug Pharmacology +5

Sulfur analogs of psychotomimetic agents. 2. Analogs of (2,5-dimethoxy-4-methylphenyl)- and of (2,5-dimethoxy-4-ethylphenyl)isopropylamine

Journal of Medicinal Chemistry May 1, 1983 Peyton Jacob, Alexander T. Shulgin 18 citations

Two thio analogues of the psychotomimetic drugs DOM and DOET were synthesized and tested in humans. The 5-thio isomers are more potent than the 2-thio isomers but are about ten times less potent than the original sulfur-free drugs. The dithio analogue of DOM showed no central activity at a dose roughly 50 times the effective dose of DOM.

DOI: 10.1021/jm00359a021 Isopropylamine Psychotomimetic Thio- Tetrahydrothiophene +5

Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane

Journal of Medicinal Chemistry January 1, 1992 Robert Oberlender, Robert C. Pfaff, Michael P. Johnson et al. 17 citations

Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.

DOI: 10.1021/jm00080a001 Lysergic acid diethylamide Stereochemistry Agonist Substituent +4

Resolution and absolute configuration of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, a potent hallucinogen analog

Journal of Medicinal Chemistry April 1, 1979 David E. Nichols, Ronald W. Woodard, Bruce A. Hathaway et al. 16 citations

The hallucinogen analogue DMCPA was separated into its two mirror-image forms using a crystallization technique. By comparing the optical properties of these forms to a related compound of known structure, the absolute configuration of the (-) isomer was determined to be (1R,2S) and the (+) isomer (1S,2R). Earlier work showed the (-) isomer causes selective behavioral effects in cats and mice; this study found it also selectively raises body temperature in rabbits compared to the (+) isomer. This stereoselective activity supports a model linking the active binding conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

DOI: 10.1021/jm00190a021 Citation Altmetrics Computer science Icon +3

Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

Journal of Medicinal Chemistry September 16, 1999 Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh et al. 15 citations

The R enantiomers of two rigid tryptamine analogues show a 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers, with no distinction based on the position of the oxygen group. The R enantiomers of both compounds have nearly identical affinities at the agonist-labeled receptor, while racemic versions of related compounds have about one-tenth the affinity. In rats trained to discriminate LSD or DOI from saline, the R enantiomers are about equipotent to DOI but about 10-fold less potent than LSD. One compound produced only partial substitution even at a dose nearly 5-fold higher than for the active R enantiomer. The results suggest these compounds would possess LSD-like psychopharmacology in humans.

DOI: 10.1021/jm990325u Enantiomer Stereochemistry Tryptamine Ligand biochemistry +7

Sulfur analogs of psychotomimetic agents. 30. Ethyl homologs of mescaline and their monothioanalogs

Journal of Medicinal Chemistry July 1, 1984 Peyton Jacob, Alexander T. Shulgin 14 citations

All possible monothio analogues of mono-, di-, and triethoxy homologues of mescaline were synthesized and tested in humans. Modifications at the ring position para to the ethylamine chain, using a sulfur atom, a longer alkyl chain, or both, produce compounds with high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also made and tested. Propyl homologues retain high potency, but a butyl group, with or without sulfur, reduces activity. Meta-ethyl or meta-thio analogues retain some central action, while diethoxy and especially triethoxy homologues are relatively inactive as psychotomimetic drugs.

DOI: 10.1021/jm00373a013 Mescaline Psychotomimetic Citation Social media +4

Synthesis of Phenethylamines Related to Mescaline as Possible Psychotomimetic Agents1

Journal of Medicinal Chemistry May 1, 1963 Orrie M. Friedman, Krishnan Parameswaran, Sumner Burstein 14 citations

Several new phenethylamine compounds structurally related to mescaline were synthesized and tested for psychotomimetic activity in animals. The synthesis involved introducing sulfur and phosphorus substituents into the phenethylamine backbone. Some of the new compounds produced behavioral effects in animals similar to those of mescaline, suggesting they may act as hallucinogens. The work aimed to explore how chemical modifications to the mescaline structure affect psychoactive potency.

DOI: 10.1021/jm00339a002 Mescaline Phenethylamines Chemistry Psychotomimetic +2

Phenylalkylamines with potential psychotherapeutic utility. 2. Nuclear substituted 2-amino-1-phenylbutanes

Journal of Medicinal Chemistry February 1, 1980 Robert T. Standridge, Henry G. Howell, Hugh A. Tilson et al. 13 citations

A series of new chemical compounds similar to a known hallucinogen were synthesized and tested in animals. Most of the analogues showed low hallucinogenic potential. The compounds were compared with a reference substance in a behavioral model that distinguishes hallucinogenic from non-hallucinogenic drugs. The chemical structures and their effects are discussed.

DOI: 10.1021/jm00176a010 Hallucinogen Butane Stereochemistry Chemical synthesis +2

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogs of hallucinogenic phenethylamines: lack of LSD-like biological activity

Journal of Medicinal Chemistry September 1, 1984 David E. Nichols, K. P. Jadhav, Robert Oberlender et al. 12 citations

Three new compounds—cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine—were synthesized as rigid versions of hallucinogenic phenylisopropylamines. In rats trained to distinguish LSD from saline, the cis compound did not produce LSD-like effects at doses up to 20 mg/kg. Both trans compounds partially mimicked LSD at 5 mg/kg or higher. In contrast, a related cyclopropylamine compound fully substituted for LSD. The trans cyclobutylamines were about 50 to 75 times less potent than the cyclopropylamine analogue. The lack of full generalization suggests these cyclobutylamines either produce different effects from LSD or lack discriminative effects entirely.

DOI: 10.1021/jm00375a004 Mescaline Phenethylamines Hallucinogen Biological activity +2