Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines
Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka, Medhane G Cumbay, Val J. Watts, Eric L. Barker, David E. Nichols
Journal of Medicinal Chemistry October 19, 2000 DOI: 10.1021/jm000339w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with in vivo behavioral assays and in vitro radioligand competition assays Peer reviewed |
|---|---|
| Population | Rats (LSD-trained and LY293284-trained) |
| Interventions | psilocin and 5-methoxy-DMT |
| Topics | Serotonin |
| Keywords | Tryptamines Hallucinogen Partial agonist Pharmacology 5-HT Receptor Intrinsic activity Biological activity Stereochemistry |
| Citations | 132 |
| Key findings | Fluorination of hallucinogenic tryptamines generally reduces 5-HT1A receptor affinity and functional potency, except for 4-fluoro-5-methoxy-DMT, which shows enhanced 5-HT1A activity, suggesting a possible role for this receptor in tryptamine effects. |
Abstract
A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT(1A) agonist activity and in vitro radioligand competition assays for their affinity at 5-HT(2A), 5-HT(2C), and 5-HT(1A) receptor sites. Functional activity at the 5-HT(2A) receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT(1A) receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT(1A) agonist activity, with potency greater than that of the 5-HT(1A) agonist 8-OH-DPAT. The ED(50) of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT(1A) agonist LY293284 was 0.17 micromol/kg, and the K(i) at [(3)H]8-OH-DPAT-labeled 5-HT(1A) receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT(2A/2C) receptor affinity or intrinsic activity. Affinity at the 5-HT(1A) receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT(1A) receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT(2A) receptor activation, the present results suggest a possible role for involvement of the 5-HT(1A) receptor with tryptamines.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 82
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers Biological Psychiatry April 26, 2014
- Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors Biological Psychiatry May 9, 2012
- Psychedelics and the Human Receptorome PLoS One 2010
- The hallucinogenic world of tryptamines: an updated review. Archives of Toxicology August 1, 2015
and 77 more in the library
Cites 7
- Human psychopharmacology of N,N-dimethyltryptamine Behavioural Brain Research December 1, 1995
- Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist The Journal of Organic Chemistry July 1, 1994
- Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Journal of Medicinal Chemistry 1996
- Characterization of the Discriminative Stimulus Properties Induced by 5‐HT1and 5‐HT2Agonists in Rats Pharmacology & Toxicology February 1, 1989
- 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
and 2 more in the library