Journal of Medicinal Chemistry - The Consciousness Library

Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class

Journal of Medicinal Chemistry October 1, 1986 David E. Nichols, Andrew J. Hoffman, Robert Oberlender et al. 189 citations

A new phenethylamine derivative, 1-(1,3-benzodioxol-5-yl)-2-butanamine, was synthesized in both racemic and enantiomerically pure forms, along with the related compound MDA. In rats trained to discriminate LSD from saline, only the racemate and R-(-) enantiomer of the alpha-methyl homologue, and the S-(+) enantiomer of the alpha-ethyl primary amine, produced stimulus generalization; other enantiomers and N-methyl derivatives did not. Human studies indicated the N-methyl derivative was nonhallucinogenic but had a novel psychoactive effect. The authors propose this compound as the prototype of a new pharmacological class, termed entactogens, potentially useful in facilitating psychotherapy.

DOI: 10.1021/jm00160a035 Enantiomer Phenethylamine Stereochemistry

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

Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues.

Journal of Medicinal Chemistry December 26, 2014 Andrew P Riley, Chad E Groer, David Young et al. 115 citations

Salvinorin A, a compound from the leaves of Salvia divinorum, activates κ-opioid receptors and could be a basis for treating substance abuse. Researchers synthesized several derivatives with modified furan rings to better understand how this part of the molecule binds to the receptor. Functional assays showed that smaller substitutions are preferred, indicating the furan ring fits into a tight part of the binding pocket. The most potent analogue reduced drug-seeking behavior in an animal model of relapse without causing sedation, a common side effect of other κ-opioid agonists.

DOI: 10.1021/jm501521d Full text

1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

Journal of Medicinal Chemistry September 21, 2006 Thomas H. Mclean, Jason C. Parrish, Michael R Braden et al. 115 citations

A series of rigid analogues of the hallucinogenic phenethylamine 2C-B was synthesized to determine the active shape these molecules adopt when binding to the 5-HT(2A) receptor. Computer docking predicted that one benzocyclobutene analogue, (R)-2, would be the most potent. Chemical resolution and X-ray crystallography confirmed this: (R)-2 was equipotent to LSD in rats trained to discriminate LSD from saline, making it one of the most potent and selective compounds yet tested in this assay. The compound also acted as a functionally selective agonist at the 5-HT(2A) receptor, showing 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are linked to arachidonic acid production, such selective agonists might lack the intoxicating properties of LSD.

DOI: 10.1021/jm060656o Full text LSD Psychopharmacology: neuropharmacology Drug action Brain chemistry +15

Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups

Journal of Medicinal Chemistry January 1, 1996 Aaron Monte, Danuta Marona‐lewicka, Matthew Parker et al. 106 citations

A series of eight new phenylalkylamine derivatives with conformationally restricted dihydrofuran rings were synthesized and tested in rats. One compound, 7b, substituted for LSD in a drug discrimination assay with an ED50 of 61 nmol/kg and bound to 5-HT2 receptors with nanomolar to subnanomolar affinity, making it among the most potent hallucinogen-like phenylalkylamines reported. All compounds with a hydrophobic substituent para to the alkylamine side chain matched or exceeded the activity of flexible parent compounds. The results suggest the dihydrofuran rings model the active binding conformations of methoxy groups and provide information about agonist binding topography in serotonin 5-HT2 receptors.

DOI: 10.1021/jm960199j Mescaline Serotonin Hallucinogen Ketanserin +11

Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists

Journal of Medicinal Chemistry January 26, 2001 James J. Chambers, Deborah Kurrasch‐orbaugh, Matthew Parker et al. 98 citations

Modifying the 2,5-oxygen substituents typical of hallucinogenic amphetamines such as DOB enhanced ligand affinity for 5-HT(2A) and 5-HT(2C) agonist binding sites. Restricting flexible 2,5-dimethoxy groups into fused dihydrofuran rings generally increased potency. Pure enantiomers were synthesized via enantiospecific acylation, ketone reduction, and N-deprotection. R-enantiomers bound with slightly higher affinity than S-enantiomers at both receptors and generally showed greater potency in functional studies. Aromatization of dihydrofuran rings further increased affinity and potency. Most compounds were partial agonists with intrinsic activities of 60-80%. Compounds with a fully aromatic linear tricyclic nucleus are among the highest-affinity 5-HT(2A) receptor ligands reported.

DOI: 10.1021/jm000491y Enantiomer Stereochemistry Potency Stereoselectivity +8

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

A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor

Journal of Medicinal Chemistry December 1, 1998 Matthew Parker, Danuta Marona‐lewicka, Virginia L. Lucaites et al. 69 citations

A novel (benzodifuranyl)aminoalkane compound was synthesized and evaluated for activity at the 5-HT2A receptor. The compound exhibited extremely potent activity, with a Ki value of 0.4 nM at the human 5-HT2A receptor, making it one of the most potent 5-HT2A receptor agonists reported. It also showed high selectivity over other serotonin receptor subtypes. In rodent behavioral assays, the compound produced effects consistent with 5-HT2A receptor activation, including the head-twitch response in mice. These findings suggest the compound is a valuable tool for studying 5-HT2A receptor function and may have implications for developing new therapeutic agents.

DOI: 10.1021/jm9803525 Citation Library science Pharmacy Computer science +2

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

Thieno[3,2-b]- and Thieno[2,3-b]pyrrole Bioisosteric Analogues of the Hallucinogen and Serotonin Agonist N,N-Dimethyltryptamine

Journal of Medicinal Chemistry March 1, 1999 Joseph B. Blair, Danuta Marona‐lewicka, Arthi Kanthasamy et al. 63 citations

Two thienopyrrole compounds, designed as structural replacements for the indole ring in N,N-dimethyltryptamine (DMT), were synthesized and tested. Neither compound produced LSD-like effects in rats trained to discriminate LSD or DOI, even at high doses. However, both fully substituted for a 5-HT1A receptor agonist and caused behaviors consistent with 5-HT1A activation, such as serotonin syndrome and salivation. At the 5-HT2A receptor, one compound had twice the affinity of the other, while at 5-HT2B and 5-HT2C receptors the pattern reversed. The thienopyrrole replacement thus failed to mimic DMT's activity at 5-HT2 receptors but enhanced activity at the 5-HT1A receptor, indicating that serotonin receptor subtypes respond differently to subtle electronic changes in the aromatic ring system.

DOI: 10.1021/jm980692q Serotonin Tryptamines Hallucinogen Bioisostere +12

Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)

Journal of Medicinal Chemistry May 1, 1991 Michael P. Johnson, Stewart Frescas, Robert Oberlender et al. 53 citations

Two experimental compounds—racemic and enantiomeric forms of 1-(3-methoxy-4-methylphenyl)-2-aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11)—produced effects in rats similar to those of MDMA and related drugs, substituting with high potency in drug-discrimination tests for MDMA and its analog. However, unlike MDMA, these compounds did not cause serotonin neurotoxicity: rat brain monoamine levels remained unchanged one week after a single high dose or two weeks after repeated dosing, and serotonin transporter binding was unaffected. The compounds also potently inhibited serotonin uptake in vitro, with the S enantiomer of 6 being most active.

DOI: 10.1021/jm00109a020 MDMA Methylenedioxy Methamphetamine Stereochemistry +2

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

2,3-Dihydrobenzofuran analogs of hallucinogenic phenethylamines

Journal of Medicinal Chemistry January 1, 1991 David E. Nichols, Scott E. Snyder, Robert Oberlender et al. 45 citations

Two new compounds related to hallucinogenic amphetamines were synthesized and tested in rats trained to discriminate LSD from saline, and for their ability to bind to serotonin 5-HT2 receptors in rat brain tissue. The compounds, which contain a rigid dihydrofuran ring, showed activity similar to their more flexible counterparts. Adding a bromine atom to the compounds contributed 2.4–3.2 kcal/mol of binding energy, 2–3 times more than expected from hydrophobic binding alone, suggesting that the bromine's effect cannot be explained solely by its hydrophobicity and that an unknown receptor interaction is involved.

DOI: 10.1021/jm00105a043 Phenethylamines Hallucinogen Pharmacology Stereochemistry +1

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

Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients

Journal of Medicinal Chemistry February 1, 1975 Charles F. Barfknecht, David E. Nichols, William J. Dunn 42 citations

The hallucinogenic potency of certain amphetamines and phenethylamines in humans may be related to their lipophilicity, as measured by the 1-octanol-water partition coefficient. For 11 amphetamines, these coefficients were measured directly, and for 17 additional amines they were estimated using published Hansch pi constants. The analysis suggests that an ideal log P value for psychotomimetic activity in humans may fall between 2.89 and 3.72.

DOI: 10.1021/jm00236a023 Mescaline Phenethylamines Partition coefficient Psychotomimetic +5

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 Richard A Glennon, Stephen M. Liebowitz, Elizabeth C. Mack 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

Synthesis and evaluation of 2,3-dihydrobenzofuran analogs of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: drug discrimination studies in rats

Journal of Medicinal Chemistry February 1, 1986 David E. Nichols, Andrew J. Hoffman, Robert Oberlender et al. 34 citations

Two new chemical analogues of the hallucinogen DOM were created and tested in rats trained to distinguish LSD from saline. Both analogues produced LSD-like effects, but only at doses more than ten times higher than DOM. The authors suggest this weakened activity may be due to the orientation of oxygen atoms in the analogues, which may not fit a specific binding site on the brain receptor.

DOI: 10.1021/jm00152a022 Citation Icon Altmetrics Social media +3

Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR spectroscopy.

Journal of Medicinal Chemistry February 1, 1981 G P Migliaccio, T L Shieh, S R Byrn et al. 34 citations

NMR spectroscopy reveals that the side-chain conformations of bufotenin and psilocin differ in solution. In water, both compounds have similar populations of trans and gauche rotamers. In chloroform, bufotenin shows a slight preference for the trans rotamer, while psilocin strongly favors the gauche form, stabilized by about 1 kcal/mol, possibly due to a weak hydrogen bond. The difference in biological activity between the two compounds is largely explained by their different basicities: the amino group pKa of psilocin is 8.47, compared to 9.67 for bufotenin, which affects their partitioning behavior.

DOI: 10.1021/jm00134a016 Full text

Modified ibogaine fragments: synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5, 6-hexahydroazepino[4,5-b]benzothiophenes.

Journal of Medicinal Chemistry November 5, 1998 S M Efange, D C Mash, A B Khare et al. 33 citations

Five new compounds derived from a fragment of ibogaine were synthesized and tested for their ability to bind to brain receptors and transporters. All five showed 8 to 10 times stronger binding to the dopamine transporter than ibogaine itself. Two compounds were more potent than ibogaine at the serotonin transporter, while the others were weaker. The compounds generally had weak binding to dopamine D1 and D2 receptors, but two showed moderate binding to dopamine D3 receptors. All had weak binding to opioid receptors and NMDA receptors. These derivatives may serve as useful substitutes for ibogaine in addiction therapy.

DOI: 10.1021/jm980156y Full text Drug discovery New compounds Novel compounds Synthesized +18

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

Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists.

Journal of Medicinal Chemistry September 22, 2022 Christian B M Poulie, Eline Pottie, Icaro A Simon et al. 32 citations

The serotonin 2A receptor (5-HT2AR) is responsible for the psychedelic effects of certain drugs, which show promise for treating neuropsychiatric conditions. This work examined how a series of compounds, including 25CN-NBOH, signal through two pathways: Gαq and β-arrestin. Disrupting the interaction with a specific amino acid, Ser1593×36, reduced both pathways' potency and efficacy, with Gαq signaling more strongly affected. This led to the creation of the first effective β-arrestin-biased 5-HT2AR agonists (4a-b and 6e-f), which prefer the β-arrestin pathway over Gαq relative to LSD.

DOI: 10.1021/acs.jmedchem.2c00702 Full text Neuroscience Psychedelic-medicine Pharmacology Mental-health +1

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