TY - JOUR
T1 - Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands
AU - Keck, Thomas M.
AU - Banala, Ashwini K.
AU - Slack, Rachel D.
AU - Burzynski, Caitlin
AU - Bonifazi, Alessandro
AU - Okunola-Bakare, Oluyomi M.
AU - Moore, Martin
AU - Deschamps, Jeffrey R.
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Newman, Amy Hauck
N1 - Funding Information:
This research was funded by the NIDA Intramural Research Program. T.M.K., A.K.B., R.D.S., A.B. and O.M.O.-B. were supported by NIH Postdoctoral Intramural Research Training Award (IRTA) Fellowships. C.B. was supported by an NIH Post-baccalaureate IRTA Fellowship. Crystallographic studies were supported by NIDA contract Y1-DA1101. HEK 293 cells were generously provided by Dr. David Sibley of NINDS. Thanks to Ben Free and Theresa Kopajtic for help in developing the radioligand binding assay. Thanks to Catherine Schweppe and Michael Ellenberger for technical assistance with the radioligand binding studies. Thanks to Elie Pommier for technical assistance with the metabolic studies.
PY - 2015/6/11
Y1 - 2015/6/11
N2 - The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.
AB - The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.
KW - 1,2,3-Triazole
KW - Bioisoteric replacement
KW - Click chemistry
KW - Dopamine D3 receptor
KW - Metabolic stability
KW - Structure-activity relationships
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U2 - 10.1016/j.bmc.2015.01.017
DO - 10.1016/j.bmc.2015.01.017
M3 - Article
C2 - 25650314
AN - SCOPUS:84930864874
SN - 0968-0896
VL - 23
SP - 4000
EP - 4012
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 14
ER -