(+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist.
A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).
Sit
Sing-Yuen
SY
Department of Neuroscience, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492-7660, USA. sits@bms.com
Xie
Kai
K
Jacutin-Porte
Swanee
S
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
Wong
Henry
H
Zhu
Juliang
J
Krishnananthan
Subramaniam
S
Gao
Qi
Q
Verdoorn
Todd
T
Johnson
Graham
G
D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D009284:Naphthols / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism
D018491:Dopamine Agonists; D007546:Isoquinolines; D009284:Naphthols; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C097827:dinapsoline; D000242:Cyclic AMP