Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines
Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka, Medhane 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.