Bioinspired Honokiol Analogs and Their Evaluation for Activity on the Norepinephrine Transporter

Abstract

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with γ-aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 µM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.

In Vitro and In Silico Studies of Neolignans from Magnolia grandiflora L. Seeds against Human Cannabinoids and Opioid Receptors

“…The presence of these neolignans in the other species of the genus Magnolia , including M. officinalis , M. obovata , and M. virginiana , has led to the use of supplements prepared from these extracts as anti-depressants, analgesics, aphrodisiacs, and appetite suppressants or stimulants [ 17 ]. Earlier studies [ 24 ] have indicated that 1 and 2 could potentiate γ-aminobutyric acid A (GABA A ) receptors and could act as positive allosteric modulators (PAMs); however, these neolignans have shown no direct interaction with the norepinephrine transporter [ 25 ]. In 2004, Kong et al, evaluated the MAO inhibitory potential of 2 and 3 using rat brain mitochondria; however, no significant rat brain MAO inhibitory activity was noted [ 26 ].…”