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]quinol ines (TB[f]Q), varying with respect to the position of the thiophene r elative to the benzo[f]quinoline core and the nature and position of t he substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thien o[3,2-c]B[f]Q regioisomers bearing a small alkyl (C1-C3) substituent a t the 2 position were potent (K-i < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compou nds were resolved and found to exhibit a high level of enantiospecific ity 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. thia-5 -azacyclopent-1-ena[c]phenanthrene-9,10-diol (5) emerged as the compou nd with the best overall in vivo profile in terms of potency (ED50 = 0 .04 mu mol/kg) and safety.