1-Cyclohexylpiperazine: Receptor Ligand Applications

1-Cyclohexylpiperazine serves as a key building block for synthesising pharmaceuticals, pesticides, and bioactive molecules. Within the pharmaceutical sector, it serves as a core fragment for candidate drugs such as σ-receptor ligands and MC4/CCR4 receptor antagonists. In organic synthesis, it is commonly prepared by reacting piperazine with bromocyclohexane under reflux conditions in acetonitrile/potassium carbonate, yielding high-purity products upon column chromatography purification.

Vibrational spectroscopy and conformation of 1-cyclohexylpiperazine

1-Cyclohexylpiperazine (1-chpp) molecule has been part of many different scientific studies. For example, a series of 1-chpp and its derivatives were investigated as potent and selective antagonists of the human MC4, CCR4 receptors and potential myocardial imaging agents . It has been also used to synthesize of potential analgesic agents and some of its derivatives have been studied in the cancer researches. The B3LYP density functional model exhibits good performance on electron affinities, excellent performance on bond energies and reasonably good performance on vibrational frequencies and geometries of organic compounds. A detailed quantum chemical investigation will aid in making assignments to the fundamental normal modes of 1-Cyclohexylpiperazine and clarifying the obtained experimental results for this molecule. In this work, the stable conformers of 1-chpp have been studied within the framework of DFT. FT-IR and Raman spectra with the vibrational spectral assignments of 1-chpp have been reported. The vibrational wavenumbers and structural parameters have been also calculated for the most stable conformer at B3LYP level of theory using 6-31G basis set. According to the literature, experimental data on the geometric structure of 1-chpp is not available. However, some geometric parameters for piperazine and cyclohexene molecules were identified both experimentally and theoretically in previously reported studies.[1]

The magnitude of dihedral angles, D(20;18;32;3) and D(32;3;4;5) for the optimized 1-chpp in the e–e form are found to be as 175.5° and 179.4°. Moreover, these dihedral angles are found as 175.3° and 179.8° for the a–e form of 1-Cyclohexylpiperazine. Up to our knowledge, the vibrational assignments of 1-chpp in the region of 4000–200 cm−1 have not been reported in the literature. 1-chpp (C10H20N2) consists of 32 atoms, so it has 90 normal vibrational modes and it belongs to the point group C1 with only identity symmetry operation. It is difficult to determine 1-chpp’s vibrational assignments in the observed spectrum due to its low symmetry. We performed the experimental and the theoretical vibrational analysis of 1-Cyclohexylpiperazine for the first time. The structural parameters, IR-Raman frequencies and intensities–activities of vibrational bands of 1-chpp were calculated with B3LYP methods and 6-31G(d) basis set for e–e and a–e conformers. In order to make a comparison with experimental wavenumbers, we calculated root mean square deviation (RMSD) based on the calculation. Based on the gas phase energy calculations and the obtained experimental–theoretical rmsd results indicate that is the most stable conformer of the 1-Cyclohexylpiperazine molecule. Any differences observed between the experimental and the calculated wavenumbers could be due to the fact that the calculations have been performed for single molecule in the gaseous state contrary to the experimental values recorded in the presence of intermolecular interactions. Henceforth, the assignments made at B3LYP/6-31++G level of theory with only reasonable deviations from the experimental values seem feasible.

4-(Tetralin-1-yl)- and 4-(Naphthalen-1-yl)alkyl Derivatives of 1-Cyclohexylpiperazine

Several high-affinity σ2 receptor ligands with low selectivity over the σ1 receptor were found in this class of 1-cyclohexylpiperazines. The best results were obtained when the intermediate chain length was of three or five methylenes. Nevertheless, high-affinity σ1 receptor ligands were present in this class. Among the other compounds, the tetralin and the naphthalene, both bearing a four-methylene intermediate chain, emerged as highly σ1-selective ligands. The presence of the piperazine ring implemented the N-binding opportunities, resulting in more complicated SAfiR studies, but the presence of an aromatic bicycle, sometimes methoxy-substituted, led to a better selectivity. The structural features for binding the σ2 receptor seem to be very similar to those for the σ1 receptor, differing only in chain length and orientation of the terminal moiety. The existence of a secondary σ2 binding site was supported by the high affinity of these 1-cyclohexylpiperazines and was corroborated by the low affinity and antagonist activity of AC927. In a next work in progress, we are exploring whether the piperazine N atom or the cyclohexyl ring is essential for σ2 receptor binding in this class of ligands. C24H38N2O·2HCl was confirmed as the most selective σ2 receptor ligand, but high activity was displayed by naphthalene derivatives too. On the basis of the functional assay, C24H38N2O·2HCl and related 1-cyclohexylpiperazines are claimed as novel σ2 agonist agents. Moreover, the σ2 agonist activity of it was confirmed by our preliminary results, displaying its high cytotoxic and antiproliferative effects both in human SK-N-SH neuroblastoma cells and rat C6 glioma cells (from the Interlab Cell Line Collection).  Therefore, C24H38N2O·2HCl and related σ2 agonists are proposed as a class of potential antineoplastic and PET diagnosis agents.[2]

References

[1]Alver, Ö., & Parlak, C. (2010). Vibrational spectroscopic investigation and conformational analysis of 1-cyclohexylpiperazine. Journal of Molecular Structure, 975(1–3), 85–92.

[2]Berardi, Francesco et al. “4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma2 activity.” Journal of medicinal chemistry vol. 47,9 (2004): 2308-17. doi:10.1021/jm031026e

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