2. Academic Validation
  3. Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines

Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines

  • Psychopharmacology (Berl). 2023 Jan;240(1):115-126. doi: 10.1007/s00213-022-06279-2.
Adam L Halberstadt 1 2,  Dino Luethi 3,  Marius C Hoener 4,  Daniel Trachsel 5,  Simon D Brandt 6,  Matthias E Liechti 3
Affiliations

Affiliations

  • 1 Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093-0804, USA. ahalberstadt@ucsd.edu.
  • 2 Research Service, VA San Diego Healthcare System, San Diego, CA, USA. ahalberstadt@ucsd.edu.
  • 3 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Pharmaceutical Sciences, University Hospital Basel and University of Basel, Basel, Switzerland.
  • 4 pRED, Roche Innovation Center Basel, Neuroscience Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • 5 ReseaChem GmbH, Burgdorf, Switzerland.
  • 6 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
PMID: 36477925 DOI: 10.1007/s00213-022-06279-2
Abstract

Rationale: 4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs.

Objectives: The present studies were conducted to examine the structure-activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by psychedelic drugs in mice. The HTR is commonly used as a behavioral proxy in rodents for human psychedelic effects and can be used to discriminate hallucinogenic and non-hallucinogenic 5-HT2A agonists.

Methods: HTR dose-response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL/6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence.

Results: 2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT2A receptor. Binding and functional studies confirmed that the compounds have nanomolar affinity for 5-HT2 receptor subtypes and act as partial agonists at 5-HT2A.

Conclusions: In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT2A receptor. These findings further support the classification of 2C-T compounds as psychedelic drugs.

Keywords

5-HT2A receptor; Hallucinogen; Head-twitch response; Mice; Phenethylamine; Psychedelic.

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