title: Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands.
abstract: 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.
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Thomas M
authors: TM
authors: Keck
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Ashwini K
authors: AK
authors: Banala
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Rachel D
authors: RD
authors: Slack
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Caitlin
authors: C
authors: Burzynski
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Alessandro
authors: A
authors: Bonifazi
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States.
authors: Oluyomi M
authors: OM
authors: Okunola-Bakare
authors: Naval Research Laboratory, Code 6930, 4555 Overlook Avenue, Washington, DC 20375, United States.
authors: Martin
authors: M
authors: Moore
authors: Naval Research Laboratory, Code 6930, 4555 Overlook Avenue, Washington, DC 20375, United States.
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205 United States.
authors: Rana
authors: R
authors: Rais
authors: Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205 United States; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, United States.
authors: Barbara S
authors: BS
authors: Slusher
authors: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States. Electronic address: anewman@intra.nida.nih.gov.
authors: Amy Hauck
authors: AH
authors: Newman
mesh_terms: D000818:Animals; D057930:Click Chemistry / Q000379:methods*; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D057809:HEK293 Cells; D006801:Humans; D008658:Inactivation, Metabolic; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D050637:Receptors, Dopamine D3 / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D008024:Ligands; D050637:Receptors, Dopamine D3; D054852:Small Molecule Libraries; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System
keywords: 1,2,3-Triazole; Bioisoteric replacement; Click chemistry; Dopamine D3 receptor; Metabolic stability; Structure–activity relationships
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