Methylated Analogues of Methyl (R)-4-(3,4-Dichlorophenylacetyl)- 3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696) as Highly Potent κ-Receptor Agonists:  Stereoselective Synthesis, Opioid-Receptor Affinity, Receptor Selectivity, and Functional Studies

Analogues of the κ-receptor agonist methyl (R)-4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696, <BO>6</BO>) bearing an additional methyl substituent in the side chain are synthesized and evaluated for their κ-receptor affinity and selectivity. A key step in the synthesis is the stereoselective reductive amination of the ketones <BO>9</BO>, <BO>18</BO>, and <BO>19 </BO>with pyrrolidine and NaBH<INF>3</INF>CN, which succeeds only in the presence of the Lewis acid Ti(OiPr)<INF>4</INF>. Whereas the BOC-substituted ketone <BO>9</BO> affords the unlike and like diastereomers of <BO>10</BO> in a ratio of 70:30, the diastereoselectivity during the reductive amination of the butyl and phenyl substituted ketones <BO>18 </BO>and <BO>19</BO> is enhanced to 85:15 (butyl derivative) and >95:&lt;5 (phenyl derivative) in favor of the unlike diastereomers. In receptor binding studies using the radioligand [³H]U-69,593 the (S,S)-configured methyl carbamate (S,S)-<BO>14</BO> reveals the highest κ-receptor affinity (K<INF>i</INF> = 0.31 nM) within this series, even exceeding the lead κ-agonist <BO>6</BO> (GR-89,696). A slightly reduced κ-receptor affinity is observed with the propionamide (S,S)-<BO>13</BO> (K<INF>i</INF> = 0.67 nM). The κ-receptor affinity of piperazines with acyl or alkoxycarbonyl residues at both nitrogen atoms (<BO>11</BO>, <BO>13</BO>, <BO>14</BO>) decreases in the order (S,S) > (R,R) > (S,R) > (R,S). The methyl carbamate (S,S)-<BO>14 </BO>discloses a unique activity profile also binding at μ-receptors in the subnanomolar range (K<INF>i</INF> = 0.36 nM). In a functional assay, i.e., by measuring acetylcholine release in rabbit hippocampus slices, the agonistic effects of the methyl carbamate (S,S)-<BO>14</BO> and the propionamide (S,S)-<BO>13 </BO>are demonstrated. Only weak κ- and μ-receptor affinities are found with the butyl- and phenyl-substituted piperazines <BO>22</BO> and <BO>23</BO>. However, considerable σ<INF>1</INF>-receptor affinity is determined for the enantiomeric, unlike-configured butyl derivatives (R,S)-<BO>22 </BO>and (S,R)-<BO>22</BO> with K<INF>i</INF>-values of 40.2 nM and 81.0 nM, respectively.