| Abstract
| - A series of substituted9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines(TB[f]Q), varyingwith respect to the position of the thiophene relative to thebenzo[f]quinoline core and thenature and position of the substituent on the thiophene, were preparedand evaluated for theiraffinity and selectivity for the dopamine D1-like receptor. Thethieno[3,2-c]B[f]Qregioisomersbearing a small alkyl (C1−C3) substituent at the 2 position werepotent (Ki< 20 nM) andselective (D2/D1 > 50) D1 agonists with close to full agonist activity(IA > 85%). The compoundswere resolved and found to exhibit a high level of enantiospecificityin their interaction withthe D1 receptor. Selected compounds were tested in vivoin the 6-OHDA rodent model ofParkinson's disease and for their liability to produce seizure-likeactivities 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 overallin vivo profile in terms of potency(ED50 = 0.04 μmol/kg) and safety.
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