S. Soukara et al., Methylated analogues of methyl (R)-4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696) as highly potent kappa-receptor agonists: Stereoselective synthesis, opioid-receptor affinity, receptor selectivity, and functional studies, J MED CHEM, 44(17), 2001, pp. 2814-2826
Analogues of the kappa -receptor agonist methyl (R)-4-(3,4-dichlorophenylac
etyl)-3-(pyrrolidin-1-ylmethyl)piperazine-l-carboxylate (GR-89,696, 6) bear
ing an additional methyl substituent in the side chain are synthesized and
evaluated for their kappa -receptor affinity and selectivity. A key step in
the synthesis is the stereoselective reductive amination of the ketones 9,
18, and 19 with pyrrolidine and NaBH3CN, which succeeds only in the presen
ce of the Lewis acid Ti-(OiPr)(4). Whereas the BOC-substituted ketone 9 aff
ords the unlike and like diastereomers of 10 in a ratio of 70:30, the diast
ereoselectivity during the reductive amination. of the butyl and phenyl sub
stituted ketones 18 and 19 is enhanced to 85:15 (butyl derivative) and > 95
:<5 (phenyl derivative) in favor of the unlike diastereomers. In receptor b
inding studies using the radioligand [H-3]U-69,593 the (S,S)-configured met
hyl carbamate (S,S)-14 reveals the highest kappa -receptor affinity (K-i =
0.31 nM) within this series, even exceeding the lead kappa -agonist 6 (GR-8
9,696). A slightly reduced kappa -receptor affinity is observed with the pr
opionamide (S,S)-13 (K-i = 0.67 nM). The kappa -receptor affinity of pipera
zines with acyl or alkoxycarbonyl residues at both nitrogen atoms (11, 13,
14) decreases in the order (S,S) > (RR) > (SR) > (R,S). The methyl carbamat
e (S,S)-14 discloses a unique activity profile also binding at mu -receptor
s in the subnanomolar range (K-i = 0.36 nM). In a functional assay, i.e., b
y measuring acetylcholine release in rabbit hippocampus slices, the agonist
ic effects of the methyl carbamate (S,S)-14 and the propionamide (S,S)-13 a
re demonstrated. Only weak kappa- and mu -receptor affinities are found wit
h the butyl- and phenyl-substituted piperazines 22 and 23. However, conside
rable sigma (1)-receptor affinity is determined for the enantiomeric, unlik
e-configured butyl derivatives (R,S)-22 and (SR)-22 with K-i-values of 40.2
nM and 81.0 nM, respectively.