Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines

Dec 2, 2000Journal of medicinal chemistry

How adding fluorine to ring structures affects the drug actions of hallucinogenic tryptamines

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Abstract

Fluorinated analogues of tryptamines generally show reduced hallucinogenic activity, with one compound, 4-fluoro-5-methoxy-DMT, exhibiting high 5-HT(1A) agonist activity.

All fluorinated tryptamine analogues tested exhibited attenuated or abolished hallucinogen-like activity in behavioral assays.
Functional activity at the 5-HT(2A) receptor was confirmed for all synthesized compounds.
4-fluoro-5-methoxy-DMT demonstrated significantly enhanced affinity and potency at the 5-HT(1A) receptor compared to other analogues.
Affinity at the 5-HT(1A) receptor was generally reduced for all compounds except for 4-fluoro-5-methoxy-DMT.
The findings suggest that while activation of the 5-HT(2A) receptor is linked to hallucinogenic effects, there may also be a role for the 5-HT(1A) receptor in the activity of tryptamines.

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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.

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Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines

Abstract

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