Physostigmine analogues

Fig. 12.4 Stedman s series of physostigmine analogues, including miotin (racemic).

Carbamylated enzymes that carry a much longer (C=0)-N-substituent, have a considerably longer off-rate. The N-heptyl analogue of physostigmine (see below) has a tVi of 11 days, but this was attributed to a hydrophobic interaction between the chain and the enzyme. 

Physostigmine has limited medicinal use since it has serious side-effects, and as a result it has only been used in the treatment of glaucoma. However, simpler analogues have been made and have been used in the treatment of myasthenia gravis and as an antidote to curare. These analogues retain the important features mentioned above. Miotine (Fig. 11.51) still has the necessary carbamate, aromatic, and tertiary... 

The therapeutic use is (like pilocarpine) to decrease the intraocular pressure in the eye in glaucoma. Furthermore, intestinal peristalsis is stimulated and physostigmine is used to remove intestinal atonia after operations. The effect of physostigmine on striated muscles is also important. As an acetylcholine inhibitor physostigmine (and synthetic analogues) is used in the treatment of myasthenia gravis and as an antidote in the case of overdosage of tubocurarine used as a muscle relaxant in complete anaesthesia. 

The alkaloid physostigmin (1) and its analogues bearing pyrrolo[2.3-b]pyrrolidine structural units have attracted attention because of their activity as cholinesterase inhibitors. A short synthesis of compound 2 possessing a pyrrolopyrrolidine skeleton includes the following reactions, in which 4-hydroxycoumarine (X, cf problem 76) is used as starting material ... 

When aryl carbamate AChEls, such as physostigmine and its analogues, bind to the catalytic site of AChE, hydrolysis of the carbamate occurs. This transesterifies the serine residue with carbamic acid, forming what is termed a carbamylated enzyme. The rate of carbamylation follows the order of carbamic acid esters > methylcarbamic acid esters > dimethylcarbamic acid esters (40). 

Let us return to the blocking of AChase by physostigmine, the first location of a drug receptor on an enzyme (p. 28). Synthesis of analogues showed that the... 

Several modifications, including the use of dual electrode coulometric detection, a high speed reciprocating pump and the A,A-dimethyl analogue of physostigmine as the internal standard, decreased the LoD to 25ngL (RSD=19.6%, 4mL... 

The task for medicinal chemists was to produce analogues of physostigmine with similar activity and fewer side effects (especially on CNS) and with better chemical stability. Miotine (Fig. 16.9) followed physostigmine as a first synthetic AChE inhibitor. It is still prone to chemical hydrolysis and its non-permanently charged tertiary... 

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