Local anaesthetics receptor site

The inner pore and local anaesthetic receptor site... 

FIG. 5. Lamotrigine binding to the local anaesthetic receptor site in transmembrane segments IIIS6 and IVS6 of the rat brain type IIA Na channel. Side view of the proposed location of the lamotrigine binding site within the pore. 

The common features of the local anaesthetic receptor site suggest that novel Na channel blocking drugs could be developed to fit this site that might have higher affinity and specificity than presently available compounds. Consistent with this idea, the novel compound Bill 890 CL, a complex ether of benzoyl and modified benzomorphan moieties, is a potent Na channel blocker binding at the local anaesthetic receptor site with a of 50 nM for the inactivated state (Carter et al 2000). It is aimed for neuroprotective therapy in the treatment of stroke and possibly neurodegenerative diseases. 

Local anaesthetics and barbiturates appear to prevent the changes in ion permeability which would normally result from the interaction of acetylcholine with its receptor. They do not, however, bind to the acetylcholine binding site. It is believed that they bind instead to the part of the receptor which is on the inside of the cell membrane, perhaps binding to the ion channel itself and blocking it. 

The water-solubility characteristics are predominantly provided by the corresponding hydrophilic centre of the molecule. Undoubtedly, this constitutes a cardinal factor in the transportation of the drug substance i.e., local anaesthetic) to the membrane and once slipping inside the cell, subsequently moves on to the desired receptor site. Besides, hydrophilicity also aids towards the binding of the drug molecule ultimately to the receptor. 

Fig. 5.1. A diagramatic sketch of the binding phenomenon of an ester-type local anaesthetic drug to a receptor site by various physical forces.

It has been proved with substantial evidence that local anaesthetics essentially containing amide fimctional moities show a tendency to afford a reasonably stronger bondage with the receptor site. 

Noradrenaline is, to some extent, a selective agonist for a receptors, whereas adrenaline shows little selectivity between a and p receptors. A goal of Oj selectivity is to cause vasoconstriction without affecting the heart or lungs. Noradrenaline is used to selectively promote vasoconstriction in cases of acute hypotension. It is also sometimes incorporated in injeaions of local anaesthetics in order to prolong their action dose to the site of injection. 

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