Journal of Medicinal Chemistry

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

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

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

Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands

Journal of Medicinal Chemistry July 1, 2003 James J. Chambers, Jason C. Parrish, Niels Jensen et al. 27 citations

Conformationally constrained tetrahydronaphthofurans were designed to study the optimal shape of the 2-aminoethyl moiety in phenethylamine-type serotonin 5-HT(2A) receptor agonists. In vitro assays showed that benzofuran-containing analogues (6a and 6b) had significantly higher affinity for 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors than benzodihydrofuran-containing compounds. The most potent compound, 6b, had K(i) values of 2.6 nM at 5-HT(2A) and 1.1 nM at 5-HT(2C) cloned rat receptors. Despite high affinity, these naphthofuran compounds lacked high intrinsic activity at the 5-HT(2A) receptor in the phosphoinositide hydrolysis assay. Compound 6b failed to substitute for LSD in a rat drug discrimination assay, typical for low intrinsic activity compounds. Conformational constraint produced high-affinity partial agonists, but full receptor activation requirements remain unidentified.

DOI: 10.1021/jm030064v Serotonin Stereochemistry Phenethylamine Intrinsic activity +6

Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of 3,4-(Methylenedioxy)amphetamine (MDA)

Journal of Medicinal Chemistry February 24, 1998 Matthew Parker, Danuta Marona‐lewicka, Deborah M. Kurrasch et al. 25 citations

Adding a methyl group to the 2 or 5 position of the ring of MDA produces compounds that are more potent and more selective than MDA itself at releasing serotonin in rat brain tissue. The 2-methyl and 5-methyl derivatives were tested in rats trained to distinguish serotonin-releasing drugs from saline, confirming their activity in living animals. These compounds are among the most potent serotonin-releasing agents known and may serve as leads for developing antidepressants that work by releasing serotonin rather than blocking its reuptake.

DOI: 10.1021/jm9705925 Serotonin Methylenedioxy Pharmacology Hallucinogen +13

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