Disjunctive approaches

FIGURE 16.35 3-PPP is a result of the disjunctive approach applied to pergolide. ... 

FIGURE 19.1 Neostigmine and rivastigmine are the result of disjunctive approach applied to physostigmine. 

Simplification of the original lead compound is especially appropriate for natural substances. This approach, known as the disjunctive approach (see Chapter 16) consists of a molecular dissection that deletes functions, structural elements, or cycles. Classical examples of disjunctive approaches are found in the pruning of the acetylcholinesterase inhibitor physostigmine to yield neostigmine and, later one, rivastigmine (Figure 19.1) or the change from somatostatin to a simplified hexapeptide. ... 

Other examples of disjunctive approaches are collected in Table 19.1. The main result of the methodology is the identification of the portions of the molecule that are essential for the expected biological activity and of those that are not. 

Dopamine autoreceptor agonists. The discovery of 3-(3-hydroxyphenyl)-A -/i-propyl piperidine (( )-3-PPP), a centrally acting dopamine receptor agonist with selectivity for dopaminergic autoreceptors, offers a potential alternative to neuroleptics in the treatment of schizophrenia. The structure of ( )-3-PPP (Fig. 14.31) can be considered as resulting from a disjunctive approach applied to pergolide. Surprisingly, an increase in the... 

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