Preparation and Pharmacological Characterization of trans-2-Amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes as D<INF>2</INF>-like Dopamine Receptor Agonists

The present work reports the synthesis of trans-2-amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (<BO>4a</BO><BO>−</BO><BO>f</BO>, <BO>5a</BO><BO>−</BO><BO>f</BO>) as a continuation of our studies to better understand the significance of the halo substituent in the trans-1-phenyl-2-aminoindane series and to extend knowledge of the monophenolic ligands of DA receptors. The affinity of the new compounds and related methoxylated precursors (<BO>10</BO>−<BO>15</BO> and <BO>18</BO>−<BO>23</BO>) was estimated in vitro by displacement of [³H]SCH23390 (for D<INF>1</INF>-like receptors) or [³H]YM-09-151-2 (for D<INF>2</INF>-like receptors) from homogenates of porcine striatal membranes. The results indicate that unsubstituted amines <BO>4a</BO>, <BO>5a</BO>, <BO>10</BO>, and <BO>11</BO> are poorly effective at DA receptors. The introduction of two n-propyl groups on the nitrogen atom (compounds <BO>14</BO>, <BO>15</BO>, <BO>4c</BO>, and <BO>5c</BO>) and N-allyl-N-methyl- or N-methyl-N-propyl- substitution (compounds <BO>20</BO><BO>−</BO><BO>23</BO>, <BO>4e</BO>, <BO>4f</BO>, <BO>5e</BO>, <BO>5f</BO>) increased the D<INF>2</INF>-like affinities and selectivity. The D<INF>2</INF>-like agonistic activity of selected compounds <BO>15</BO>, <BO>20</BO>, <BO>21</BO>, <BO>4e</BO>, <BO>5c</BO>, and <BO>5e</BO> was proved by evaluating their effects on the cyclic guanosine monophosphate (cGMP) content in rat neostriatal membranes. All tested compounds displayed a potential dopamine D<INF>2</INF>-like agonist profile decreasing basal levels of cGMP. The selective D<INF>2</INF>-like agonism of compounds <BO>20</BO> and <BO>5e</BO> was proved by their effects on basal striatal adenylyl cyclase activity.