Synthesis and SAR exploration of dinapsoline analogues.
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.
Sit
Sing-Yuen
SY
Department of Neuroscience Drug Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. sits@bms.com
Xie
Kai
K
Jacutin-Porte
Swanee
S
Boy
Kenneth M
KM
Seanz
James
J
Taber
Matthew T
MT
Gulwadi
Amit G
AG
Korpinen
Carolyn D
CD
Burris
Kevin D
KD
Molski
Thaddeus F
TF
Ryan
Elaine
E
Xu
Cen
C
Verdoorn
Todd
T
Johnson
Graham
G
Nichols
David E
DE
Mailman
Richard B
RB
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
D001372:Aza Compounds; D007546:Isoquinolines; D009284:Naphthols; C097827:dinapsoline; D005461:Fluorine; D000262:Adenylyl Cyclases