| Abstract
| - Analogues of the κ-receptor agonist methyl (R)-4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696, 6) bearing an additional methyl substituent inthe side chain are synthesized and evaluated for their κ-receptor affinity and selectivity. Akey step in the synthesis is the stereoselective reductive amination of the ketones 9, 18, and19 with pyrrolidine and NaBH3CN, which succeeds only in the presence of the Lewis acid Ti(OiPr)4. Whereas the BOC-substituted ketone 9 affords the unlike and like diastereomers of10 in a ratio of 70:30, the diastereoselectivity during the reductive amination of the butyl andphenyl substituted ketones 18 and 19 is enhanced to 85:15 (butyl derivative) and >95:<5 (phenylderivative) 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)-14 reveals the highest κ-receptoraffinity (Ki = 0.31 nM) within this series, even exceeding the lead κ-agonist 6 (GR-89,696). Aslightly reduced κ-receptor affinity is observed with the propionamide (S,S)-13 (Ki = 0.67 nM).The κ-receptor affinity of piperazines with acyl or alkoxycarbonyl residues at both nitrogenatoms (11, 13, 14) decreases in the order (S,S) > (R,R) > (S,R) > (R,S). The methyl carbamate(S,S)-14 discloses a unique activity profile also binding at μ-receptors in the subnanomolarrange (Ki = 0.36 nM). In a functional assay, i.e., by measuring acetylcholine release in rabbithippocampus slices, the agonistic effects of the methyl carbamate (S,S)-14 and the propionamide(S,S)-13 are demonstrated. Only weak κ- and μ-receptor affinities are found with the butyl-and phenyl-substituted piperazines 22 and 23. However, considerable σ1-receptor affinity isdetermined for the enantiomeric, unlike-configured butyl derivatives (R,S)-22 and (S,R)-22with Ki-values of 40.2 nM and 81.0 nM, respectively.
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