LOCAL ANAESTHETICS

Some local anaesthetics have a formal similarity to acetylcholine, although it is possible that they act directly on ion-channels and block sodium ion conductance. The initial leads for these compounds were derived from the anaesthetic action of the alkaloid, cocaine 3.24, which, despite its addictive properties, became quite a useful drug in the late nineteenth century. Structural simplification led to the development of procaine 3.25 in 1905 and to compounds such as tetracaine 3.26 and benzocaine 3.27. Another alkaloid isogramine 3.28 was also shown to have local anaesthetic action. Lidocaine (xylocaine) 3.29 introduced in 1948, which is widely used as a local anaesthetic in dentistry and in minor surgery such as the insertion of stitches, was developed from this.

Lidocaine and its analogues are easily synthesized. Structure:activity studies revealed the requirement for a lipophilic portion (the aromatic ring) connected by a flexible chain to a hydrophilic unit. X-ray studies revealed the role of the methyl groups in twisting the aromatic ring out of the plane of the amide.