title: Synthesis and SAR exploration of dinapsoline analogues.
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.
authors.affiliation: Department of Neuroscience Drug Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. sits@bms.com
authors.forename: Sing-Yuen
authors.initials: SY
authors.lastname: Sit
authors.forename: Kai
authors.initials: K
authors.lastname: Xie
authors.forename: Swanee
authors.initials: S
authors.lastname: Jacutin-Porte
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boy
authors.forename: James
authors.initials: J
authors.lastname: Seanz
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Taber
authors.forename: Amit G
authors.initials: AG
authors.lastname: Gulwadi
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Korpinen
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burris
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Elaine
authors.initials: E
authors.lastname: Ryan
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
authors.forename: Todd
authors.initials: T
authors.lastname: Verdoorn
authors.forename: Graham
authors.initials: G
authors.lastname: Johnson
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D005461:Fluorine / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D007546:Isoquinolines; D009284:Naphthols; C097827:dinapsoline; D005461:Fluorine; D000262:Adenylyl Cyclases