Synthesis and SAR exploration of dinapsoline analogues

Sing Yuen Sit, Kai Xie, Swanee Jacutin-Porte, Kenneth M. Boy, James Seanz, Matthew T. Taber, Amit G. Gulwadi, Carolyn D. Korpinen, Kevin D. Burris, Thaddeus F. Molski, Elaine Ryan, Cen Xu, Todd Verdoorn, Graham Johnson, David E. Nichols, Richard B. Mailman

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Abstract

Dinapsoline is a full D1 dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was determined to have the S-(+) configuration, and the opposite enantiomer is essentially devoid of biological activity. Taken together, dinapsoline has significant metabolic and pharmacological advantages over previous D1 agonists. In an attempt to define the structure-activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B′, C and D ring) of dinapsoline were synthesized. It was found that affinity for both D1and D2 receptors was decreased by most substituents on the A, B′, and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.

Original languageEnglish (US)
Pages (from-to)715-734
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number4
DOIs
StatePublished - Feb 15 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Sit, S. Y., Xie, K., Jacutin-Porte, S., Boy, K. M., Seanz, J., Taber, M. T., Gulwadi, A. G., Korpinen, C. D., Burris, K. D., Molski, T. F., Ryan, E., Xu, C., Verdoorn, T., Johnson, G., Nichols, D. E., & Mailman, R. B. (2004). Synthesis and SAR exploration of dinapsoline analogues. Bioorganic and Medicinal Chemistry, 12(4), 715-734. https://doi.org/10.1016/j.bmc.2003.11.015