A 28‑day regimen (0.5 mg kg⁻¹, daily i.p.) evaluated tolerance (EPM) and dependence (withdrawal scoring after abrupt cessation). Brain tissue (hippocampus, prefrontal cortex) was examined histologically (H&E, Fluoro‑Jade C) and for markers of neuroinflammation (Iba‑1, GFAP immunostaining).
Adult C57BL/6J mice (n = 12/group) received i.p. CTN (0.1, 0.5, 2 mg kg⁻¹) or vehicle 30 min before testing. Time spent in open arms, entries into open arms, and total locomotion were recorded (ANY‑maze software). the substance couchtuner
| Receptor | K i (nM) | Functional Outcome | |----------|-------------------|-------------------| | 5‑HT₂A | | Full antagonist (IC₅₀ = 17 nM) | | D₂ | 45 ± 5 | Partial agonist (E max ≈ 38 %, EC₅₀ = 62 nM) | | 5‑HT₁A | 210 ± 18 | Agonist (E max ≈ 64 %, EC₅₀ = 210 nM) | | σ₁ | 980 ± 70 | Partial agonist (E max ≈ 45 %) | | α₂‑adrenergic | > 10 000 | Negligible | A 28‑day regimen (0
CTN was synthesized in three steps (Scheme 1). Starting from 4‑hydroxy‑benzaldehyde (1.00 g, 8.2 mmol), a Knoevenagel condensation with malonic acid yielded 4‑hydroxy‑cinnamic acid (2) (80 % yield). Subsequent catalytic hydrogenation over Pd/C afforded 4‑hydroxy‑phenylpropionic acid (3) (85 % yield). Finally, coupling of 3 with N,N‑dimethyl‑ethylenediamine using EDCI/HOBt in DMF gave CTN as a pale‑yellow solid (71 % yield). Purity (> 99 %) was confirmed by HPLC‑UV (λ = 254 nm) and ^1H/^13C NMR (CDCl₃). CTN (0
CTN is a white, hygroscopic solid (mp = 212–214 °C). The ^1H‑NMR (400 MHz, CDCl₃) displayed characteristic signals: aromatic protons (δ 7.10–6.78 ppm, 4 H), methylene protons adjacent to the amide (δ 3.62 ppm, 2 H, d, J = 7.2 Hz), N‑dimethyl groups (δ 2.30 ppm, s, 6 H). The compound showed moderate aqueous solubility (≈ 12 mg mL⁻¹ at pH 7.4) and a calculated polar surface area (PSA) of 84 Ų, compatible with CNS penetration.
The search for compounds that can simultaneously modulate multiple neurotransmitter systems while retaining a favorable safety profile remains a central challenge in neuropsychopharmacology. Classical anxiolytics (e.g., benzodiazepines) and cognitive enhancers (e.g., cholinesterase inhibitors) often suffer from limited efficacy, tolerance, or undesirable side‑effects. Phenethylamine‑based scaffolds have historically yielded a broad spectrum of psychoactive agents, ranging from stimulants (amphetamine) to psychedelics (LSD, psilocybin) and atypical antipsychotics (clozapine). Recent high‑throughput screening of a 12 000‑compound phenethylamine library identified couchtuner (hereafter ) as a compound with a unique poly‑pharmacological profile: high affinity for 5‑HT₂A and D₂ receptors, moderate 5‑HT₁A agonism, and σ₁ partial agonism. The present work aims to (i) describe the synthesis and physicochemical properties of CTN, (ii) delineate its receptor binding and functional activity, (iii) evaluate its pharmacokinetics and brain penetration, and (iv) assess its behavioral effects in rodent models relevant to anxiety and cognition.
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