Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT                         2C                          Receptor

Christopher T. Wild; Joanna M. Miszkiel; Eric A. Wold; Claudia A. Soto; Chunyong Ding; Rachel M. Hartley; Mark A. White; Noelle C. Anastasio; Kathryn A. Cunningham; Jia Zhou

doi:10.1021/acs.jmedchem.8b00401

Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor

Christopher T. Wild
, Joanna M. Miszkiel
, Eric A. Wold
, Claudia A. Soto
, Chunyong Ding
, Rachel M. Hartley
, Mark A. White
, Noelle C. Anastasio
, Kathryn A. Cunningham
, Jia Zhou

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

An impaired signaling capacity of the serotonin (5-HT) 5-HT _2C receptor (5-HT _2C R) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT _2C R signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT _2C R positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT _2C R but not the 5-HT _2A R cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT _2C R structure. Compound 16 modulated 5-HT _2C R-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT _2C R agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.

Original language	English (US)
Pages (from-to)	288-305
Number of pages	18
Journal	Journal of medicinal chemistry
Volume	62
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00401
State	Published - Oct 1 2019

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.8b00401

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Wild, C. T., Miszkiel, J. M., Wold, E. A., Soto, C. A., Ding, C., Hartley, R. M., White, M. A., Anastasio, N. C., Cunningham, K. A., & Zhou, J. (2019). Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor Journal of medicinal chemistry, 62(1), 288-305. https://doi.org/10.1021/acs.jmedchem.8b00401

Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor . / Wild, Christopher T.; Miszkiel, Joanna M.; Wold, Eric A. et al.
In: Journal of medicinal chemistry, Vol. 62, No. 1, 01.10.2019, p. 288-305.

Research output: Contribution to journal › Article › peer-review

Wild, CT, Miszkiel, JM, Wold, EA, Soto, CA, Ding, C, Hartley, RM, White, MA , Anastasio, NC , Cunningham, KA & Zhou, J 2019, ' Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor ', Journal of medicinal chemistry, vol. 62, no. 1, pp. 288-305. https://doi.org/10.1021/acs.jmedchem.8b00401

Wild CT, Miszkiel JM, Wold EA, Soto CA, Ding C, Hartley RM et al. Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor Journal of medicinal chemistry. 2019 Oct 1;62(1):288-305. doi: 10.1021/acs.jmedchem.8b00401

Wild, Christopher T. ; Miszkiel, Joanna M. ; Wold, Eric A. et al. / Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor In: Journal of medicinal chemistry. 2019 ; Vol. 62, No. 1. pp. 288-305.

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title = " Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT 2C Receptor ",

abstract = " An impaired signaling capacity of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT 2C R signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT 2C R positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT 2C R but not the 5-HT 2A R cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT 2C R structure. Compound 16 modulated 5-HT 2C R-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT 2C R agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.",

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Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT _2C Receptor

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