1. Synthesis and SAR exploration of dinapsoline analogues
- Author
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Carolyn D. Korpinen, James Seanz, David E. Nichols, Amit G. Gulwadi, Kevin D. Burris, Thaddeus F. Molski, Cen Xu, Richard B. Mailman, Matthew T. Taber, Kai Xie, Kenneth M. Boy, Sing Yuen Sit, Todd A. Verdoorn, Swanee Jacutin-Porte, Elaine Ryan, and Graham Johnson
- Subjects
Agonist ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Dinapsoline ,Naphthols ,Biochemistry ,Chemical synthesis ,Dihydrexidine ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Molecular Biology ,Cells, Cultured ,Aza Compounds ,Molecular Structure ,Chemistry ,Organic Chemistry ,Biological activity ,Dopamine receptor binding ,Fluorine ,Isoquinolines ,Rats ,Molecular Medicine ,Enantiomer ,medicine.drug ,Adenylyl Cyclases - Abstract
Dinapsoline is a full D(1) 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 D(1) 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 D(1)and D(2) 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.
- Published
- 2003