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Psychedelic-like Activity of Norpsilocin Analogues - PubMed

  • ️Mon Jan 01 2024

Psychedelic-like Activity of Norpsilocin Analogues

Alexander M Sherwood et al. ACS Chem Neurosci. 2024.

Abstract

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT2A) in vitro but differ in their 5-HT2A-mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the N-methyl group of norpsilocin by a single methyl group, to give the corresponding secondary N-ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED50 = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier tert-butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series in vitro demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT2A, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.

Keywords: head twitch response; mice; norpsilocin; psychedelic; tryptamines.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1

Tryptamine natural products with disparate bioavailability or psychoactivity, highlighting the role of hydroxyl and amine substitutions.

Figure 2
Figure 2

Synthesis of norpsilocin-related analogues with nomenclature and corresponding partition coefficient (cLogP) values calculated using Chemdraw Professional 22.2 (2023, PerkinElmer Informatics).

Figure 3
Figure 3

Dose–response and time-course data for the HTR induced by norpsilocin analogues. (A) Dose–response curves for effects on the HTR (n = 5–6 mice/dose) and representative time-course plots for HTR activity of (B) 4-HO-NET, (C) 4-HO-NPT, and (D) 4-HO-NALT.

Figure 4
Figure 4

pKi (−log Ki) heatmap plot for inhibition constants (Ki, nM) of norpsilocin analogues in competition binding assays for human 5-HT receptors and select sites. Light gray boxes represent inhibition constants >1 μM from full dose–response experiments, and dark gray boxes indicate <50% inhibition in the primary radioligand binding screen. Each inhibition constant was derived from n = 2–3 experiments with triplicate determinations, and values for 95% confidence intervals are shown below each Ki value. Radioligands used, reference control compound used, and control Ki values for each receptor appear in

Table S2

while data for other hits across the series is shown in

Figure S5

.

Figure 5
Figure 5

Heatmap plots of the potencies (A, pEC50, EC50) and maximal effects (B, Emax) of norpsilocin analogues in Gαq-mediated calcium flux assays at human 5-HT2 receptors. pEC50 = −log EC50 values. EC50 values with 95% confidence intervals noted below in parentheses for 2–3 experiments with triplicate determinations are listed in each box. “x” denotes no activity, and “*” with italicized text denotes potentially ambiguous EC50 and/or Emax values. Concentration–response curves are shown in

Figure S6

.

Figure 6
Figure 6

Functional agonist activity screening heatmap plots for norpsilocin analogues at 5-HT1, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors using the GPCR Tango assay measuring β-arrestin recruitment. “x” denotes no activity up to 50 μM, and “*” with italicized text denotes activity trends with ambiguous EC50 and/or Emax values. If a stable top was not reached by 2 consecutive points, the maximum effect observed is reported as Emax. Assays represent 1–2 experiments run in triplicate. The associated concentration–response curves are shown in

Figure S7

.

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