Receptors without enzymatic activity

One important implication of the compartmentation, however, is the restrictions imposed on chemical compounds interacting with specific receptors. It is not sufficient for a potential bioactive substance to possess the shape and polarity demanded by the receptor. It must also be capable of entering the receptor environment. This may mean that the compound will have to penetrate the bilayer membrane and enter the appropriate compartment of the receptor. Throughout this journey the compound may well traverse areas of high enzymatic activity and thus be subject to metabolic transformations which may activate, deactivate or be without effect with regard to the influence on the target receptor. 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

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