TY - JOUR
T1 - Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators
AU - Chen, Jianping
AU - Garcia, Erik J.
AU - Merritt, Christina R.
AU - Zamora, Joshua C.
AU - Bolinger, Andrew A.
AU - Pazdrak, Konrad
AU - Stafford, Susan J.
AU - Mifflin, Randy C.
AU - Wold, Eric A.
AU - Wild, Christopher T.
AU - Chen, Haiying
AU - Anastasio, Noelle C.
AU - Cunningham, Kathryn A.
AU - Zhou, Jia
N1 - Publisher Copyright:
© 2023 American Chemical Society
PY - 2023/7/27
Y1 - 2023/7/27
N2 - The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.
AB - The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.
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U2 - 10.1021/acs.jmedchem.3c00908
DO - 10.1021/acs.jmedchem.3c00908
M3 - Article
C2 - 37462530
AN - SCOPUS:85166362871
SN - 0022-2623
VL - 66
SP - 9992
EP - 10009
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 14
ER -