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Synthesis, pharmacological characterization, and binding mode analysis of 8-hydroxy-tetrahydroisoquinolines as 5-HT7 receptor inverse agonists

Camilla B. Chan, Eline Pottie (UGent) , Icaro A. Simon, Adrian G. Rossebø, Matthias M. Herth, Kasper Harpsøe, Jesper L. Kristensen, Christophe Stove (UGent) and Christian B. M. Poulie
(2025) ACS CHEMICAL NEUROSCIENCE. 16(3). p.439-451
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Abstract
The serotonin 7 receptor (5-HT7R) regulates various processes in the central nervous system, including mood, learning, and circadian rhythm control, among others. Receptor activation can lead to activation of the G alpha s protein and a subsequent increase of intracellular cyclic adenosine monophosphate (cAMP). Receptor interaction with inverse agonists results in a decrease of basal cAMP levels and therefore a downstream effect of reduced neuronal excitability and neurotransmission. Recently, pellotine (1a), a Lophophora alkaloid, was unexpectedly shown to be an inverse agonist of the 5-HT7R. Therefore, we evaluated close analogs of compound 1a, both naturally occurring and synthetic analogs, as inverse agonists of the 5-HT7R. Functional evaluation in a GloSensor cAMP assay revealed a preference for an 8-hydroxy-6,7-dimethoxy substitution pattern over 6,7,8-trimethoxy analogs or 8-hydroxy-6,7-methylenedioxy analogs. This was supported by molecular dynamics simulations, where the 8-hydroxy substitution allowed more robust interaction with the 5-HT7R, which correlated with inverse agonism efficacy. Additionally, N-methylation (as in 1a) improved the potency of the evaluated analogs. In this series, the most potent inverse agonist was anhalidine (1b) (EC50 = 219 nM, E max = -95.4%), which lacks the 1-methyl, compared to pellotine (1a), and showed a 2-fold higher functional potency. Altogether, these results provide key insights for the further development of potent low molecular weight inverse agonists of the 5-HT7R.
Keywords
alkaloids, lophophora, peyote, 5-HT7R, inverse agonists, tetrahydroisoquinolines, INTERNATIONAL UNION, PROTEIN, SLEEP, CLASSIFICATION, ANNOUNCEMENT, DYNAMICS, DOCKING, SYSTEM, GLIDE, WATER

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MLA
Chan, Camilla B., et al. “Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists.” ACS CHEMICAL NEUROSCIENCE, vol. 16, no. 3, 2025, pp. 439–51, doi:10.1021/acschemneuro.4c00667.
APA
Chan, C. B., Pottie, E., Simon, I. A., Rossebø, A. G., Herth, M. M., Harpsøe, K., … Poulie, C. B. M. (2025). Synthesis, pharmacological characterization, and binding mode analysis of 8-hydroxy-tetrahydroisoquinolines as 5-HT7 receptor inverse agonists. ACS CHEMICAL NEUROSCIENCE, 16(3), 439–451. https://doi.org/10.1021/acschemneuro.4c00667
Chicago author-date
Chan, Camilla B., Eline Pottie, Icaro A. Simon, Adrian G. Rossebø, Matthias M. Herth, Kasper Harpsøe, Jesper L. Kristensen, Christophe Stove, and Christian B. M. Poulie. 2025. “Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists.” ACS CHEMICAL NEUROSCIENCE 16 (3): 439–51. https://doi.org/10.1021/acschemneuro.4c00667.
Chicago author-date (all authors)
Chan, Camilla B., Eline Pottie, Icaro A. Simon, Adrian G. Rossebø, Matthias M. Herth, Kasper Harpsøe, Jesper L. Kristensen, Christophe Stove, and Christian B. M. Poulie. 2025. “Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists.” ACS CHEMICAL NEUROSCIENCE 16 (3): 439–451. doi:10.1021/acschemneuro.4c00667.
Vancouver
1.
Chan CB, Pottie E, Simon IA, Rossebø AG, Herth MM, Harpsøe K, et al. Synthesis, pharmacological characterization, and binding mode analysis of 8-hydroxy-tetrahydroisoquinolines as 5-HT7 receptor inverse agonists. ACS CHEMICAL NEUROSCIENCE. 2025;16(3):439–51.
IEEE
[1]
C. B. Chan et al., “Synthesis, pharmacological characterization, and binding mode analysis of 8-hydroxy-tetrahydroisoquinolines as 5-HT7 receptor inverse agonists,” ACS CHEMICAL NEUROSCIENCE, vol. 16, no. 3, pp. 439–451, 2025.
@article{01JQ6WFR8R7G85440FRY2248HG,
  abstract     = {{The serotonin 7 receptor (5-HT7R) regulates various processes in the central nervous system, including mood, learning, and circadian rhythm control, among others. Receptor activation can lead to activation of the G alpha s protein and a subsequent increase of intracellular cyclic adenosine monophosphate (cAMP). Receptor interaction with inverse agonists results in a decrease of basal cAMP levels and therefore a downstream effect of reduced neuronal excitability and neurotransmission. Recently, pellotine (1a), a Lophophora alkaloid, was unexpectedly shown to be an inverse agonist of the 5-HT7R. Therefore, we evaluated close analogs of compound 1a, both naturally occurring and synthetic analogs, as inverse agonists of the 5-HT7R. Functional evaluation in a GloSensor cAMP assay revealed a preference for an 8-hydroxy-6,7-dimethoxy substitution pattern over 6,7,8-trimethoxy analogs or 8-hydroxy-6,7-methylenedioxy analogs. This was supported by molecular dynamics simulations, where the 8-hydroxy substitution allowed more robust interaction with the 5-HT7R, which correlated with inverse agonism efficacy. Additionally, N-methylation (as in 1a) improved the potency of the evaluated analogs. In this series, the most potent inverse agonist was anhalidine (1b) (EC50 = 219 nM, E max = -95.4%), which lacks the 1-methyl, compared to pellotine (1a), and showed a 2-fold higher functional potency. Altogether, these results provide key insights for the further development of potent low molecular weight inverse agonists of the 5-HT7R.}},
  author       = {{Chan, Camilla B. and Pottie, Eline and Simon, Icaro A. and Rossebø, Adrian G. and Herth, Matthias M. and Harpsøe, Kasper and Kristensen, Jesper L. and Stove, Christophe and Poulie, Christian B. M.}},
  issn         = {{1948-7193}},
  journal      = {{ACS CHEMICAL NEUROSCIENCE}},
  keywords     = {{alkaloids,lophophora,peyote,5-HT7R,inverse agonists,tetrahydroisoquinolines,INTERNATIONAL UNION,PROTEIN,SLEEP,CLASSIFICATION,ANNOUNCEMENT,DYNAMICS,DOCKING,SYSTEM,GLIDE,WATER}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{439--451}},
  title        = {{Synthesis, pharmacological characterization, and binding mode analysis of 8-hydroxy-tetrahydroisoquinolines as 5-HT7 receptor inverse agonists}},
  url          = {{http://doi.org/10.1021/acschemneuro.4c00667}},
  volume       = {{16}},
  year         = {{2025}},
}
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