NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds

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Abstract

We resolved 1,2-diphenylethylamine (DPEA) into its (S)- and (R)-enantiomer and used them as precursors for synthesis of (S)- and (R)-1-(1,2-diphenylethyl)piperidine, flexible homeomorphs of the NMDA channel blocker MK-801. We also describe the synthesis of the dicyclohexyl analogues of DPEA. These and related compounds were tested as inhibitors of [3H]MK-801 binding to rat brain membranes. Stereospecificity ranged between factors of 0.5 and 50. Some blockers exhibited stereospecific sensitivity to the modulator spermine. Our results may help to elucidate in more detail the NMDA channel pharmacophore.

Graphical abstract

Open-chain analogues of the prominent NMDA channel blocker MK-801 exhibit a high degree of stereoselectivity, inhibiting the binding of [3H]MK-801 to rat brain membranes (Ki).

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Introduction

The N-methyl-d-aspartate (NMDA) receptor is the most abundant receptor for the principal excitatory neurotransmitter glutamate and consists of 4 protein subunits surrounding a central channel, with various binding sites at the extracellular domain regulating permeability to Na+ and Ca2+.1 Its involvement in learning and memory, but also in pathologic conditions such as stroke, epilepsy and neurodegenerative diseases makes this receptor an attractive target of drug development.2 Analogues of the agonist glutamate itself suffer from their poor ability to cross the blood brain barrier, because they have to mimic an acidic amino acid with 3 charged functional groups. A direct attack of the ion channel by more lipophilic channel blockers appears more promising, however the best known representatives of this class are Ketamine (1b) and Phencyclidine (2), two widely abused compounds inducing psychotic side effects, and the experimental high affinity channel ligand (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, (+)-MK-801 [(+)-3].3 Examples for moderate potency NMDA channel blockers tolerated with much less psychotic side effects are 3,5-dimethyladamantan-1-amine (Memantine)4 and Dextromethorphan [(+)-4b]. To learn more about SARs at this channel binding site, we resolved racemic 1,2-diphenylethylamine (DPEA, 5a) and used its enantiomers to prepare (R)- and (S)-1-(1,2-diphenylethyl)piperidine (DEP, 6).5 Until now, both 5a and 6 had only been studied as racemic mixtures.5

The polyamines spermine and spermidine increase frequency and burst length of NMDA-induced currents in rat hippocampal neurons, by relieve from a partial block by protons, even at physiological pH.6 As a consequence, the channel is more readily accessible not only for the cations constituting its current, but also for the channel ligand MK-801 (as a secondary amine positively charged at physiological pH), thus increasing the affinity of the radioligand [3H]MK-801. Channel blockers that act similarly to MK-801 profit from increased channel accessibility to a similar extent.7 Here we demonstrate that the affinity of some of the studied stereoisomers was not influenced in the same way by spermine than that of the radioligand, suggesting that they acted in a way different from MK-801.

Section snippets

Chemistry

Commercially available (±)-5a was resolved by the method of Shinohara et al.,8 which was modified, into (+)- and (−)-enantiomers (S)- and (R)-5a, respectively. The piperidine analogues 6 were prepared from the respective 5a enantiomers with 98% ee by double alkylation9 with 1,5-dibromopentane (Scheme 1). Under optimised conditions (3 equiv of alkylating reagent, 6 equiv of K2CO3) in dry acetonitrile at ambient temperature for 3 days, the yields for the (+)-isomer (S)-6 and the (−)-isomer (R)-6

Discussion

Stereoselectivity is a characteristic feature of drug interaction with a target in a geometrically restricted micro-environment. The high stereo-factors (>30) of DPEA (5a) and DEP (6) in blocking [3H]MK-801 binding as demonstrated in this article strongly suggest the interaction with such a restricted target. Similar enantioselectivity has been reported for several 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives.23 NMR spectroscopy of (S)-5a × HCl in D2O has shown that the Ph residues preferred

Conclusion

Resolution of the NMDA channel blocker (±)-DPEA, and stereospecific synthesis of (+)- and (−)-DEP, resulted in enantiomers with highly differing potencies (stereo selectivity >30). The more potent DEP-isomer (S)-6 behaved similarly to the high affinity channel ligand MK-801, whereas the more potent DPEA-isomer (S)-5a exhibited, like (S)-Ketamine and various primary amine channel blockers, a high degree of spermine sensitivity. Our detailed SAR study on enantiomers may help at refining a

General procedures

1H, 13C (J modulated), and 19F NMR spectra were measured in CDCl3 on a Bruker Avance DRX 400, at 400.13, 100.63, and 376.5 MHz, respectively. Chemical shifts were referenced to residual CHCl3 (δH = 7.24) and CDCl3 (δC = 77.00). IR spectra were run on a Perkin–Elmer 1600 FT-IR spectrometer; liquid samples were measured as films on a silicon disc.40 Optical rotations were measured at 20 °C on a Perkin–Elmer 351 polarimeter in a 10 cm cell. TLC was carried out on 0.25 mm Silica Gel 60 F254 plates (Merck).

Acknowledgements

For parts of this study, M.L.B. received financial support from Merck KGaA (Darmstadt, Germany). Kerstin Schöringhumer, Manuel Nagl and Tanja Werle contributed to the binding data. We thank S. Felsinger for recording the NMR spectra.

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