Chemistry:RS130-180

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RS130-180, also known as N-(2-propargyloxy)-2,5-dimethoxy-4-(dimethylamino)phenethylamine, is a β-arrestin-biased serotonin 5-HT2A receptor agonist of the phenethylamine, 2C, and NBOMe families.[1][2][3] It is the NBOMe derivative in which the phenyl ring has an N,N-dimethylamino substitution at the 4 position and the 2-position methoxy group on the benzyl ring has been replaced with a propynyloxy group.[1]

The drug favors activation of β-arrestin signaling over Gq signaling.[1][2] RS130-180 is said to be useful for in-vitro studies, but to have suboptimal pharmacokinetic properties for in-vivo use.[1] β-Arrestin-biased serotonin 5-HT2A receptor agonists do not produce the head-twitch response in rodents and it is thought that they may be non-hallucinogenic in humans.[4] The cryo-EM structures of the serotonin 5-HT2A receptor with RS130-180, as well as with various serotonergic psychedelics, have been solved and published by Bryan Roth and colleagues.[1][2]

RS130-180 was first described in the literature by 2022.[2][1] It was derived from an earlier compound called ZINC000341335936, which was identified via in-silico screening of 1.6 billion molecules for serotonin 5-HT2A receptor agonism with AlphaFold2.[5] RS130-180 was developed via structural modification of ZINC000341335936 by David E. Nichols and colleagues.[5]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "The structural diversity of psychedelic drug actions revealed". Nature Communications 16 (1). March 2025. doi:10.1038/s41467-025-57956-7. PMID 40108183. Bibcode: 2025NatCo..16.2734G. 
  2. ↑ 2.0 2.1 2.2 2.3 "Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias". University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center. September 2022. https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37. "[...] Here we present 8 new cryoEM structures covering all major compound classes for the 5HT2AR including a novel arrestin biased compound RS130-180. [...]" 
  3. ↑ "Exploring Psychedelics: New Insights Into Therapeutic Mechanisms". 22 March 2025. https://evrimagaci.org/tpg/exploring-psychedelics-new-insights-into-therapeutic-mechanisms-276602. "For instance, rs130-180, a non-hallucinogenic variant, was identified as a biased agonist with therapeutic implications." 
  4. ↑ "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun 14 (1). December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107. Bibcode: 2023NatCo..14.8221W. 
  5. ↑ 5.0 5.1 "AlphaFold2 structures guide prospective ligand discovery". Science 384 (6702). June 2024. doi:10.1126/science.adn6354. PMID 38753765. PMC 11253030. Bibcode: 2024Sci...384n6354L. https://thealonlab.org/papers/science.adn6354.pdf. 



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