New approaches to the design of analgesic medicinal substances

Abstract

A gamma-pyrone derivative, comenic acid, activates the opioid-like receptor-mediated signaling pathway that modulates the NaV1.8 channels in the primary sensory neuron membrane. These channels are responsible for generation of the nociceptive signal; gamma-pyrones can therefore have a great therapeutic potential as analgesics, and this effect deserves a deeper understanding. The novelty of our approach to the design of a medicinal substance is based on a combination of the data obtained on living neurons using very sensitive physiological methods and the results of quantum-chemical calculations. This approach allows to correlate the molecular structure of gamma-pyrones with their ability to evoke a physiological response of the neuron. Comenic acid can bind two calcium cations. One of them is chelated by the carbonyl and the hydroxyl functional groups, while another one forms the salt bond with the carboxylate anion. Calcium-bound gamma-pyrones are fundamentally different in electrostatic properties from the free gamma-pyrone molecules. These two calcium ions are the key elements involved in ligand-receptor binding. It is very likely ion-ionic interactions between these cations and anionic functional groups of the opioid-like receptor that activate the latter. The calculated intercationic distance of 9.5 Å is a structural criterion for effective ligand-receptor binding of calcium-bound gamma-pyrones.

Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel

“…The ability of the tripeptides to modulate voltage sensitivity of the Na V 1.8 channel is highly specific, as the concentrations of TP1 and TP2 evoking a significant decrease in Z eff are in the nanomolar range (100 nM). Experimental data strongly suggest that both molecules are promising candidates for the role of a novel analgesic medicinal substance because our prior experience with respect to the receptor-mediated effect of comenic acid demonstrates a correlation between the specific decrease in Z eff and antinociceptive effect at the organismal level [ 1 , 4 , 5 , 18 , 19 ].…”

“…No effect of TP1 and TP2 on DRG neurite growth was detected. It indicates that the tripeptides, as opposed to earlier studied agents (comenic acid and ouabain applied at nanomolar concentrations), do not trigger the receptor- or transducer-mediated signaling cascades, the activation of which modulates the Na V 1.8 channel activation gating device [ 5 , 17 ]. This fact supports our suggestion that TP1 and TP2 bind directly to the Na V 1.8 channel due to intermolecular ion–ion bonding between positively charged guanidinium groups of the attacking peptide molecule and nucleophilic moieties of the Na V 1.8 channel.…”

“…At 3 days of culture age, the neurite growth was assessed by the morphometric method. This experimental technique is as highly sensitive as the patch-clamp method, which has been demonstrated in our prior studies [ 4 , 5 , 17 ]. The area index (AI) was calculated as the ratio of the peripheral growth zone area to the central zone area [ 4 ].…”

“…Specific ligand-receptor binding of a number of agents (comenic acid and ouabain applied at nanomolar concentrations) to the corresponding membrane targets has been demonstrated to decrease voltage sensitivity of the Na V 1.8 channel activation gating device. It has been shown to result in a selective decrease in the high-frequency component of afferent nociceptor impulse firing and, ultimately, in peripheral pain relief [ 4 , 5 ]. Analog-impulse signal conversion performed by tissue nociceptors is thus delicately modulated at the molecular level [ 6 ].…”

Role of the Rhamnosyl Residue of Ouabain in the Activation of the Na,K-ATPase Signaling Function

“…As an example, a number of short peptides were demonstrated at very low concentrations to modulate the Na V 1.8 channel activation gating system in nociceptors [19,20]. According to our data, another potentially very effective substance is EO, the Ca 2+ chelate complex of ouabain, which is also capable of modulating the Na V 1.8 channels via activation of the NKA signaling function (Kd = 1 nM) [13,21].…”