Studies of the relationship between molecular structure and hallucinogenic activity

@article{Nichols1986StudiesOT,
  title={Studies of the relationship between molecular structure and hallucinogenic activity},
  author={David E. Nichols},
  journal={Pharmacology Biochemistry and Behavior},
  year={1986},
  volume={24},
  pages={335-340}
}
  • D. Nichols
  • Published 1 February 1986
  • Chemistry, Biology
  • Pharmacology Biochemistry and Behavior

Effect of a chiral 4-alkyl substituent in hallucinogenic amphetamines.

TLDR
Evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of hallucinogenic amphetamine derivatives found that two diastereoisomeric derivatives containing a 4-(R or S)-2-butyl substituent may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.

DIFFERENTIAL INTERACTIONS OF INDOLEALKYLAMINES WITH 5-HYDROXYTRYPTAMINE RECEPTOR SUBTYPES

TLDR
It is demonstrated that hallucinogenic 4-hydroxy-indolealkylamine derivatives, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT,, recognition site, labelled by [1251]R-(-)DOI.

Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives.

TLDR
The loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

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

TLDR
It is concluded that the conformation of the amide function may directly affect binding through stereoselective interactions with a hydrophobic region on the receptor, indirectly by inducing conformational changes elsewhere in the molecule, or by a combination of these two mechanisms.

Synthesis and serotonin receptor affinities of a series of trans-2-(indol-3-yl)cyclopropylamine derivatives.

TLDR
The cyclopropylamine moiety appears to be a good strategy for rigidification of the ethylamine side chain only for tryptamines that bind to the 5-HT2C receptor isoform.

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

TLDR
This review summarizes the structure–activity relationships (SAR) of phenylalkylamines as agonist ligands for 5‐HT2A receptors and selectivity is a central theme, as is selectivity for the 5‐ HT2A receptor and for its specific signaling pathways.

Return of the lysergamides. Part II: Analytical and behavioural characterization of N6 -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ).

TLDR
Analytical characterization of powdered AL-LAD and LSZ tartrate samples and their semi-quantitative determination on blotter paper is reported to assist research communities that are interested in various aspects related to substance use and forensic identification.

Quasi‐atomistic Receptor Surrogates for the 5‐HT2A Receptor: A 3D‐QSAR Study on Hallucinogenic Substances

TLDR
A surrogate for the 5-HT2A receptor is described by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique, which allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena.

Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function

TLDR
The discriminative stimulus effects of 2C-C,2C-D, 2D-E, 2 C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine.

References

SHOWING 1-10 OF 26 REFERENCES

Stereospecific actions of DOET (2,5-dimethoxy-4-ethylamphetamine) in man.

TLDR
A comparison of the psychotropic effects of isomers of DOET (2,5-dimethoxy-4-ethylamphetamine) a "psychedelic" methoxyamphetamine, in normal human subjects is reported, indicating the psychoactive conformation of the drug.

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

TLDR
The lack of generalization to the cyclobutylamines indicates either that their discrim inative stimulus properties differ from LSD or that they lack discriminative effects.

Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane.

TLDR
Two novel hallucinogen analogues related to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP) were synthesized and evaluated in the two-lever drug discrimination paradigm by using 0.08 mg/kg of LSD as the training drug stimulus, revealing a clear difference in difference in potency and degree of LSD generalization for the two isomers.

Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane.

TLDR
The discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

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

TLDR
The two thio analogues of each of the well-known psychotomimetic drugs DOM and DOET have been synthesized and pharmacologically evaluated in man and the 5-thio isomers are more potent as psychotomIMetic agents than the 2-thios but still represent a drop of an order of magnitude in potency from the sulfur-free counterparts.

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

: In an attempt to relate the hallucinogenic potencies in man of some biologically important amphetamines and phenethylamines, the 1-octanol-water partition coefficients for 11 amphetamines were

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

TLDR
It was found that the (-) isomer selectively elicits rabbit hyperthermia when compared with the (+) isomers, lending further support to a new model which interrelates the active binding, conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

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

TLDR
Coupling constants indicate that the trans and gauche rotamers of both compounds have about equal energy in D2O, and the difference in partitioning between bufotenin and psilocin, which seems to be a major determinant of biological activity, is largely due to a difference in the basicity of the two compounds.