Easson and Stedman

In a nonchiral environment, the enantiomers of a racemate possess the same physical and chemical properties. But in the early 1930s, Easson and Stedman introduced a three-point attachment model that laid the basis for the initial understanding of stereochemical differences in pharmacological activity [13]. The authors described the differences in the bioaffinity of the enantiomers to a common site on an enzyme or receptor surface, with the receptor or enzyme needing to possess three nonequivalent binding sites to discriminate between the enantiomers. The enantiomer that interacts simultaneously with all three sites is called the eutomer (active enantiomer), whereas the other, which binds to fewer than three sites at the same time, is called the distomer (inactive enantiomer) [14]. 

However, the first mention of a three-point contact (between a chiral drug and its receptor) is found in an article by Easson and Stedman published in 1933 16W, and a year later, Max Bergmann postulated a three-point contact (involving COjH, H2N and the dipeptide linkage) between peptidases and the dipeptides hydrolyzed by them.16c) Both these publications seem to have been overlooked subsequently I thank Professors V. Prelog and H. Hirschmann, respectively, for drawing my attention to them. 

When an asymmetric center is present in a compound, it is thought that the substituents on the chiral carbon atom make a three-point contact with the receptor. Such a fit insures a very specific molecular orientation which can only be obtained for one of the two isomers (Fig. 1.3). A three-point fit of this type was first suggested by Easson and Stedman [23], and the corresponding model proposed by Beckett [24] in the case of (R)-( )-adrenaline [= (R)-( )-epinephrine]. The more active natural (R)-( )-adrenaline establishes contacts with its receptor through the three interactions shown in Fig. 1.3. 

A clear three-dimensional visualization of the means by which a receptor could differentiate between enantiomers was provided by Easson and Stedman in 1933 [25]. They proposed that three (b, c, d) of the four groups (a, b, c, d) linked to a chiral carbon atom were concerned in the process (either by normal valence forces, or by adsorptive or other forces). The receptor possessed three groups b, c and d for maximum physiological effect, the drug molecule must become attached to the receptor in such a manner that the groups b, c and d in the drug coincide respectively with b, c and d in the receptor. Such coincidence can only occur with one of the enantiomorphs and this consequently represents the more active form of the drug . The interaction (5) and non-interaction (6) were illustrated as follows ... 

This paper thus clearly defined the possibility for a three-point attachment to provide for the differentiation of enantiomeric molecules. In support of the theory, they cited results on the action of epinephrine and related compounds. Cushny had reported that (— )-epinephrine is 12-15 times as active as (+ )-epinephrine. Easson and Stedman deduced that of the four groups around the chiral center, the hydrogen played no part in the drug-receptor attachment. Thus for (—)-epinephrine the complex could be represented as 7. With the (+ )-enantiomer the hydroxyl group cannot be positioned on the hydroxyl receptor. It was suggested that a less perfect combination was possible if the hydrogen were located on the normal hydroxyl... 

This interesting paper of Easson and Stedman seems to have made almost no impression at the time of its publication and lay unrecognized until it was cited by Parascandola [24], As will be seen it also foreshadows the topic of prochirality but was not known to Ogston (I am indebted to Dr. Ogston for bringing it to my attention [26] Dr. J. Glusker had brought it to his attention). 

As noted earlier, Ogston was, in 1948, not aware of the 1933 paper by Easson and Stedman [25]. However, in that paper, those authors had taken an important conceptual step. From the three-point attachment postulated for the enantiomer of Cabcd with a receptor they supposed that the dissymmetry of 5 is abolished by replacing the group a by a second group b, the resultant molecule, represented by 16, retains unchanged that part of the structure of 5, i.e., the base bed of the tetrahedron, which is concerned with its attachment to the specific receptor and must therefore be considered capable, despite the absence of molecular dissymmetry, of... 

Interactions between ARs and their ligand moieties, distinct from those proposed by Easson and Stedman, have been suggested. For example, molecular modeling of the interaction of the a2A-AR with epinephrine has indicated that its /V-methyl group may bond with F7.38 and F7.39 (I I). However, experimental support for this interaction from mutagenesis studies is lacking. 

In this classic paper, Easson and Stedman proposed that the enantiomers of a drug that demonstrated different pharmacological activities were due to their differential binding to a defined three-dimensional site on a receptor surface (Fig. 1). The receptor would distinguish between two enantiomers only if it possessed three nonequivalent binding sites. Discrimination occurred when one enantiomer simultaneously attached to all these sites of the receptor while the other one could not. 

Inspired by Easson and Stedman s work, Dalgliesh established the three-point attachment model in 1952 to elucidate the chromatographic separation of D-/L-amino acids in cellulose paper chromatography [22]. The Dalgliesh s model was later improved by Lochmuller and Souter [23]. According to this three-point attachment model, it is necessary to have at least three attractive interactions, or two attractive and one repulsive (steric) interaction between the receptor and one of the... 

---