Three point attachment hypothesis

Fig. 195. Two-part attachment hypothesis of auxin action. The synthetic auxin 2,4-ois taken as an example similar considerations apply to native auxins. The auxin can only exercise its stimulatory effect if the molecule is attached to two sites on a carrier such as a protein. The aromatic system and the side-chain are implicated, the latter probably through a covalent bond, in this two-site attachment. At high concentrations of auxin a molecule of auxin will occupy every site on the carrier. This causes the stimulatory effect to disappear indeed, the complex may now even inhibit. Similar considerations have led to the postulation of a three-point attachment hypothesis as well as the two-point attachment hypothesis (modified from Leopold 1965).

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... 

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. 

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... 

Afterwards, based on the hypothesis that the elasticity development in plasticized PVC was due to the enhancement of micro-Brownian motions of the polymer, Doolittle, Stickney and Cheyney and Alfrey et developed the Gel Theory. They considered that the mechanical properties of a polymer were due to the elastic resistance of entangled segments of the macromolecules structured as a three-dimensional network. The plasticizer molecules which are dissolved into the polymer matrix break some points of attachment between macromolecules leading to an easier glide. Moreover,... 

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