Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines

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.

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

“…Several studies indicate that psilocin acts as an agonist at 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors. 12,13,24) Furthermore, 5-HT 2A/2C receptors are expressed in the rodent prefrontal cortex. 28,29) The hallucinogenic 5-HT 2A/2C agonist 4-iodo-2,5-dimethoxyamphetamine indirectly increases extracellular 5-HT release in the rat medial prefrontal cortex by stimulating glutamate release.…”

“…11) Recent pharmacological studies suggest that the hallucinogenic effects of psilocin and psilocybin are produced mainly because these compounds act as 5-HT receptor agonists that bind 5-HT 1A , 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors with moderate to high affinity. 12,13) The effects of psilocybin are blocked by pretreatment with the 5-HT 2A antagonist ketanserin, indicating that the hallucinogenic effects of psilocybin are mediated primarily by 5-HT 2A stimulation. [14][15][16] Thus, 5-HT 2A receptor activation is necessary for the indoleamine hallucinogenic effects of psilocybin.…”

Structure–activity relationships of serotonin 5‐HT2A agonists

“…In the study by Blair et al, 6 the effect of ring fluorination also was studied for four other tryptamines, where comparisons were made between 6-and 7-F-psilocin and 4-and 6-fluoro-5-methoxyDMT, 1, 2, 3, and 4, respectively ( Figure 3) with their nonfluorinated counterparts. Fluorination of psilocin in either the 6-or 7-position had identical effects on affinity at the rat 5-HT 2A receptor, reducing it by about one-half compared with psilocin itself.…”

Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines

“…Later suggestions focus on the 5-HT 1A receptor (Marona-Lewicka and Nichols 1995). In a particularly interesting study, Blair et al (2000) reported that ring fluorination of hallucinogenic tryptamines reduced the degree of mimicry of the stimulus effects of LSD by these drugs while at the same time diminishing their affinity for the 5-HT 1A receptor. The tryptamines, ranging from classic agents such as DMT (Sai-Halasz et al 1958) to a series of ring-and amine-substituted agents such as DPT (Fantegrossi et al 2008b;Li et al 2008), 2,5-dimethoxy-4-n-propylthiophenethylamine (Fantegrossi et al 2005), and 5-methoxy-N,N-diisopropyltryptamine (Fantegrossi et al 2006), are unquestionably hallucinogenic (Shulgin and Shulgin 1997) yet binding data regularly indicate that their highest affinity is for 5-HT 1A receptors.…”

“…Furthermore, Vollenweider et al (1996) observed that the subjective effects in normal subjects of psilocybin are blocked by ketanserin (Vollenweider et al 1996(Vollenweider et al , 1998a, an antagonist with low nanomolar affinity for 5-HT 2A receptors (Richelson and Souder 2000) and only micromolar affinity for 5-HT 1A receptors (Boess and Martin 1994). Receptor binding data provided no clue in that Blair et al (2000) observed K I values for psilocin of 49, 25, and 10 nM for 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors, respectively. Nonetheless, given the close structural similarity of 5-MeO-DMT and both psilocybin and psilocin (Fig.…”