Easson-Stedman hypothesis

Fig. 10. The postulated interaction of a-adrenoceptor agonists with the receptor. The Easson-Stedman hypothesis suggests that (R)-noradrenaline is most potent owing to its three points of attachment () to the adrenoceptor, whereas dopamine and (5)-noradrenaline are equal in activity, but less active...

Optical isomerism is the result of a dissymmetry in molecular suhstitution. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different substituents on this carbon atom interact with the receptor. The Easson-Stedman hypothesis assumes that a three-point interaction ensures stereospecificity, since only one of the enantiomers will fit the other one is capable of a two-point attachment only, as shown in figure 1.13 for the reaction with a hypothetical planar receptor. However, it is reasonable to assume that receptor stereospecificity can also undergo a change when the receptor conformation is altered by a receptor-drug interaction. 

Desoxynorepinephrine (Dopamine) Fig. 22 The Easson-Stedman hypothesis of stereoisomeric drug action. 

Another chemical property relevant to druglike behavior is stereochemistry. These are molecules that contain a chiral center (a carbon with four different attachments) causing molecules with different chiral centers to be non-superimposable. These molecules present different three-dimensional arrays to proteins, and it is presumed that this controls biological potency and efficacy. For instance, the Easson-Stedman hypothesis proposes that a biologically active enantiomer interacts with at least three points on receptor to produce biological activity. Since three points... 

Even in taking into account these newer findings, it can be speculated that the Easson-Stedman hypothesis still holds. The non-natural S(+)-adrenaline, having the wrong orientation of its benzylic hydroxyl, is unable to exchange a hydrogen bond with Ser , and achieves therefore a weaker interaction with the receptor. 

Ogston [20,21], seemingly unaware of the Easson-Stedman model, proposed a similar three-point attachment model to rationalize the observed stereoselectivity in the enzymatic transformation of symmetrical prochiral substrates, e.g., citrate and aminomalonate (Fig. 3) [22]. Similarly, Dalgleish [23], also unaware of the Easson-Stedman model [17], rationalized his observations concerning the resolution of the enantiomers of a number of amino acids on paper chromatography by a three-point attachment. In a subsequent telephone conversation with Bentley [24], Dalgleish stated that he was terribly impressed by the Ogston hypothesis. It is therefore... 

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