Conformational bioisostere

D.E., and Ferguson, A.M. Bioisosterism as a molecular diversity descriptor steric fields of single topomeric conformers. 12... 

The simple alkyl derivatives such homo-, propyl-, and /Ao-propylanatoxin-a (Fig. 7.4A) are all potent nicotinic ligands (Wonnacott et al. 1992). Most of the efforts to determine the precise stmc-tural requirements of the receptor have resulted in the synthesis of conformationally restricted derivatives (Hernandez and Rapoport 1994 Brough et al. 1992). The first bioisosteric and conformationally constrained variation of (+)-anatoxin-a found to retain mnch of the potency of the natn-ral compound was racemic ( )-pyrido[3,4-b]homotropane (PHT) (Fig. 7.4B), representing the... 

Conformational restriction was introduced into the side chain of a nonclassical serotonin bioisostere (28), a selective 5-HT and 5-HT receptor agonist) by its incorporation into a fused six-membered ring (29) (23). 

Amide bonds ean be partieularly problematie. Difficulties with solubility, bioavailabihty, and stability are eommon. At the same time, this group is frequently essential for activity due to the H-bonding they enable as well as their conformational and electronic effects. Research on amide bond replacements for peptidomimetie compounds has a rich history going back many decades and is still an area of active interest today. A very recent example of the sueeessful use of a simple amide bond bioisostere can be seen in Figure 8.10. 

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