Possible Mechanisms of Binding of Gamma- Pyridones to the Opioid-Like Receptor
Pp. 96-126 (31)
Boris V. Krylov, Ilia V. Rogachevskii, Tatiana N. Shelykh and Vera B. Plakhova
The nociceptive system codes noxious signals by increasing its impulse
firing. NaV1.8 channels play a central role in the process of primary sensory coding.
The Almers’ method is almost ideal for the study of behavior of their gating device.
Application of this method makes it possible to elucidate the mechanism of receptorcoupled
modulation of NaV1.8 channels by opioid-like receptors, which exhibit high
affinity to some gamma-pyrone and gamma-pyridone derivatives. A remarkable feature
characterizing these substances is their ability to chelate calcium. That is why opioidlike
receptors recognize these attacking molecules in physiologically appropriate
conditions by activation of a very important additional mechanism of ion-ionic
interactions switched on by attacking molecules with chelated calcium. This conclusion
is confirmed by the study of the effects of gamma-pyridone derivatives, which are
structurally very close to gamma-pyrones and, in addition, also have an ability to
The results discussed in this and the previous chapters open a new approach to solve
the problem of recognition of medicinal analgesic substances. Our quantum-chemical
calculations demonstrate that calcium chelation process plays an important role in
ligand-receptor binding and it is energetically allowed not only in vacuum but also in
the adequate physiological environment. Conclusions concerning the probable structure
of opioid-like receptor binding pocket are presented.
Ca2+ chelate complex, Gamma-pyridone derivatives, Limiting slope
procedure, NaV1.8 channels, Nociception, Opioid-like receptor, Patch-clamp
method, Quantum-chemical calculations.
I.P. Pavlov Institute of Physiology Russian Academy of Sciences St. Petersburg, Russia.