Selectivity enantiomeric potency

The introduction of asymmetry, followed by resolution, can be used to gain selectivity from a promiscuous molecule. Closely related receptors may differ only in the shape or size of their non-polar (hydrophobic) areas. Because of this, it makes sense to try to exploit differences in hydrophobic binding. Ariens (1986) exemplifies this by referring to derivatives of diphenhydramine (44, Ri = R2 = H). Table 3 is compiled from the data of Rekker et al. (1971) and shows how a 10-fold selectivity of diphenhydramine for the histamine receptor has been translated into an increase in potency and more than 100-fold selectivity towards the histamine receptor in the (-F)-methyl derivative, and to an increase in potency and more than 100-fold increase in selectivity towards the acetylcholine receptor in the (-)-r-butyl derivative. The data provide a good example of Pfeiffer s Rule (Pfeiffer, 1956) that enantiomeric potency ratios increase with potency. Many examples of this rule have been reviewed by Lehmann (1986). 

Many anaesthetics exist as enantiomeric pairs which when separated show selectivity in terms of anaesthetic potency. Studies on the action of anaesthetics at GABAa receptors have mimicked this selectivity, again... 

Optical isomers frequently exhibit quantitatively different pharmacological activities. A logical presumption is that one optical isomer of an enantiomeric pair shows better receptor interactions. Table 1-8 lists some examples of effect or potency differences of selected drugs. 

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