Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands

Xin Peng, Qi Wang, Yogesh Mishra, Jinbin Xu, David E. Reichert, Maninder Malik, Michelle Taylor, Robert T. Luedtke, Robert H. Mach

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.

Original languageEnglish
Pages (from-to)519-523
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number3
DOIs
StatePublished - 1 Feb 2015

Fingerprint

Dopamine D3 Receptors
Triazoles
Molecular modeling
Pharmacology
Ligands
Dopamine
Receptor, Serotonin, 5-HT1A
Dopamine D2 Receptors
Colforsin
Adenylyl Cyclases
Amides
Assays
Therapeutics

Keywords

  • Dopamine D receptor selective ligands
  • Dopamine receptors
  • Molecular modeling
  • Triazole

Cite this

Peng, Xin ; Wang, Qi ; Mishra, Yogesh ; Xu, Jinbin ; Reichert, David E. ; Malik, Maninder ; Taylor, Michelle ; Luedtke, Robert T. ; Mach, Robert H. / Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 3. pp. 519-523.
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abstract = "A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.",
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Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. / Peng, Xin; Wang, Qi; Mishra, Yogesh; Xu, Jinbin; Reichert, David E.; Malik, Maninder; Taylor, Michelle; Luedtke, Robert T.; Mach, Robert H.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 3, 01.02.2015, p. 519-523.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Mishra, Yogesh

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AU - Malik, Maninder

AU - Taylor, Michelle

AU - Luedtke, Robert T.

AU - Mach, Robert H.

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