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.
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.
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.
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.
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.
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.
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.
Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA
January 1, 1990
David F. Nichols, Robert Oberlender
6 citations
Evidence from drug discrimination studies suggests that MDMA and similar substances form a distinct pharmacological class called entactogens, separate from other known drug classes. Results from multiple laboratories, though still incomplete, support the view that entactogens have a unique pharmacology, as demonstrated by their discriminative stimulus properties, including training dose effects and patterns of complete substitution that differ from those of other compounds.