Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: synthesis and biological evaluation in vitro and in vivo.
A series of substituted 9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying with respect to the position of the thiophene relative to the benzo[f]quinoline core and the nature and position of the substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers bearing a small alky1 (C1-C3) substituent at the 2 position were potent (Ki < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds were resolved and found to exhibit a high level of enantiospecificity in their interaction with the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of Parkinson's disease and for their liability to produce seizure-like activities in mice. (5aR)-trans-2-Propyl-4,5,5a,6,7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (5) emerged as the compound with the best overall in vivo profile in terms of potency (ED50 = 0.04 mumol/kg) and safety.
Michaelides
M R
MR
Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Hong
Y
Y
DiDomenico
S
S
Bayburt
E K
EK
Asin
K E
KE
Britton
D R
DR
Lin
C W
CW
Shiosaki
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018491:Dopamine Agonists / Q000138:chemical synthesis*; D018492:Dopamine Antagonists / Q000378:metabolism; D005399:Fishes; D051379:Mice; D015394:Molecular Structure; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D015363:Quinolones / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D011954:Receptors, Dopamine / Q000378:metabolism; D012160:Retina / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D014316:Tritium; D015016:Yohimbine / Q000378:metabolism
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D015363:Quinolones; D011954:Receptors, Dopamine; D013876:Thiophenes; C027460:dopamine-I receptor; D014316:Tritium; D015016:Yohimbine; D016627:Oxidopamine; D000262:Adenylyl Cyclases; C095427:A 86929