R - epinephrine

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. 

Armstrong KP, Kennedy B, Watson JT, Morley-Forster PK, Yee I, Butler R. Epinephrine reduces the sedative side effects of epidural sufentanil for labour analgesia. Can J Anaesth 2002 49(l) 72-80. 

FIGURE 26.2 Interaction capacities of the natural R(-) epinephrine with a model of its receptor (after references " ). 

An alternative model of the adrenergic receptor-active site shows that natural R-( ) epinephrine (adrenaline) can establish a hydrogen bond with the Ser alcoholic group whereas this interaction is not possible with the non-natural S-(+) epinephrine (Eigure 26.3). 

FIGURE 26.3 In an adrenergic receptor model the interaction of the natural R-(—) epinephrine implies. 

Veltman Dj, van Zijderverld GA, van Dyck R. Epinephrine infusion in panic disorder a double-blind placebo-controlled study. 

Fig. 17.1 Interaction capacities of the natural R +)-epinephrine and its S(-)-antipode. In simply assuming that the natural R(+)-epinephrine establishes a three point interaction with its receptor (A) the combination of the donor-acceptor interaction, the hydrogen bond and the ionic interaction will be able to generate energies in the order 12 to 17 kcal mole that corresponds to binding constants of 10 to 10 The less active isomer, S(+)-epinephrine, may establish only a two point contact (B). The loss of the hydrogen bond interaction equals to approximately 3 kcal mole this isomer should therefore possess an approximately 100-fold lesser affinity. The experience confirms this estimate. If we consider less abstract models it becomes apparent that the less potent enantiomer is also able to develop three intermolecular bonds to the receptor, provided that it approaches the receptor in a different manner. However, the probability of this alternative binding mode to trigger the same biological response is close to null.

FIGURE 26.1 Interaction capacities of the natural R(-)-epinephrine and its S(+) antipode. In simply assuming that the natural R(-)epinephrine establishes a three-point interaction with its receptor (a) the combination of the donor-acceptor interaction, the hydrogen bond and the ionic interaction will be able to generate energies in the order 12 to 17kcal/mol, that corresponds to binding constants of 10 to The less active isomer,... 

R-(—)-epinephrine peak using a 50 p,m open tubular capillary (OTC) and a 75 /rm capillary packed with 4.1 tim nonporous bare silica particles. The diameters of the capillaries were chosen so that they would have approximately the same dead volume and electrophoretic current. It is easy to see from the plot of temporal variance versus counter flow linear velocity that much less broadening is seen in the packed capillary as compared with the large diameter open tube. 

Ii)-Adrenaline L-adrenaline, (R)-epinephrine, 4-[l-bydroxy-2-(methylamino)ethyl]-1,2-benzenediol. HO. 

---