TY - JOUR
T1 - Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2CReceptor-Positive Allosteric Modulators with Enhanced Drug-like Properties
AU - Wold, Eric A.
AU - Garcia, Erik
AU - Wild, Christopher T.
AU - Miszkiel, Joanna M.
AU - Soto, Claudia A.
AU - Chen, Jianping
AU - Pazdrak, Konrad
AU - Fox, Robert G.
AU - Anastasio, Noelle C.
AU - Cunningham, Kathryn A.
AU - Zhou, Jia
N1 - Funding Information:
This work was supported by grants R21 MH093844 (J.Z./K.A.C.), R01 DA038446 (J.Z./K.A.C.), K05 DA020087 (K.A.C.), P30 DA28821 (K.A.C.), T32 DA07287 (C.T.W. and E.A.W.), F31 DA038922 (C.T.W.), DA038446-S1 (E.J.G.), and F31 DA045511 (E.A.W.) from the National Institutes of Health, the John D. Stobo, M.D. Distinguished Chair Endowment Fund (J.Z.), the Center for Addiction Research at UTMB, R.A. Welch Foundation Chemistry and Biology Collaborative Grant from Gulf Coast Consortia (GCC) for Chemical Genomics, a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the GCC (NIGMS grant T32 GM089657-03 (C.T.W.), Sealy and Smith Foundation grant (to the Sealy Center for Structural Biology and Molecular Biophysics), and the John Sealy Memorial Endowment Fund. We thank Drs. Lawrence C. Sowers, Jason Herring, and Tianzhi Wang for the NMR spectroscopy assistance; Sonja J. Stutz assisted in some in vivo studies; Claudia M. Crawford, Carrie E. McAllister, and K.P. for conducting in vitro assays; and Marcy B. Jordan for helpful discussions during the development of this project. Receptor binding profiles and agonist functional data were generously provided by the National Institute of Mental Health Psychoactive Drug Screening Program (PDSP), contract no. HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Dr. Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/7/23
Y1 - 2020/7/23
N2 - Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
AB - Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
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U2 - 10.1021/acs.jmedchem.9b01953
DO - 10.1021/acs.jmedchem.9b01953
M3 - Article
C2 - 32567857
AN - SCOPUS:85088488557
SN - 0022-2623
VL - 63
SP - 7529
EP - 7544
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 14
ER -