0-Adrenergic agonist potency

Octopamine (4.41), which carries a p-hydroxyl group, is taken up even more readily into storage vesicles and is, in turn, released when the neuron fires. As an adrenergic agonist, octopamine is, however, only about one-tenth as active as NE therefore, it acts as a very weak neurotransmitter. Compounds such as this behave like neurotransmitters of low potency, and are called false transmitters. On the other hand, octopamine may be a true transmitter in some invertebrates, with receptors that cannot be occupied either by other catecholamines or by serotonin. 

I Relative Selectivity, Potency, and Duration I of Action of the j Adrenergic Agonists... 

To clarify some of the puzzling differential effects of sympathomimetic drugs on various tissues, in 1948 Ahlquist (76) introduced the concept of two distinct types of adrenergic receptors as defined by their responses to (1), (2), and (17), which he called alpha receptors and beta receptors. Alpha receptors were defined as those that responded in rank order of agonist potency as (2) > (1) (17). Beta receptors were defined as those responding in potency order of (17) > (2) > (1). Subsequently, /3-receptors were further divided into /3i-receptors, located primarily in cardiac tissue, and /32-adrenoceptors, located in smooth muscle and other tissues, given that (1) and (2) are approximately equipotent at cardiac... 

Substitution of the sulfonyl group also affects adrenergic activity. In general, as noted in related series (Table I), B-adrenoreceptor agonist potency decreases as the size of the sulfonyl-substituent is increased. Thus, in the guinea pig tracheal test the methyl derivative sulfonterol is three to... 

In applying this approach to the catecholamines 13-C we first considered functionalization of the aromatic ring. > However, none of our derivatives had the potency or efficacy as 3-adrenergic agonists that isoproterenol does. The most promising approach has proven to be derivatization through the amine function in the side chain of the molecules. These studies have led to the synthesis... 

Finally, there is the potency of the false transmitter itself as an adrenergic agonist. The direct actions of most of the amines vdiich have been shown to be... 

Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

It has been demonstrated that the / -selectivity is due to the para-substituents of /(-adrenoceptors. In contrast, (-)-erythro-isoetliarine, a bronchodilator. is 80 times more selective for ft -adrenergic receptors than for ft-receptors, lsoetharine contains ancr-alkyl substituent, thus producing four isomeric compounds. The (-)-erythro isomer is 100-1 old more active than the (-)-threo isomer and has more than 500 times the activity of either of the (+)-isomers and in blocking electrically stimulated spasms. In general, introduction of a-alkyl substituents on both /1-blockers and agonists provides diastereomers with increased ft-selectivity, but often with compromised potency. 

An example of agonist-specific coupling is shown in Figure 8.3. The receptor in question is the -adrenergic receptor. This receptor triggers at least two different intracellular signaling pathways Arachidonic acid is released by phospholipase A2, and inositoltriphosphate (IP3) is released by phospholipase C. These two effects are mediated by two different G proteins that couple to the same receptor. If we compare the two parameters, the three compounds norepinephrine and meta- and para-octopamine yield substantially different potencies and efficacies. If we hadn t been told otherwise, we would interpret this observation as evidence of two different receptors. In a sense, of course, different GPCR-G protein complexes are different receptors. 

Figure 8.3. Agonist-specfic coupling at aj -adrenergic receptors. The release of two different secondary messengers - arachi-donic acid and inositoltrisphosphate - is triggered by two different G proteins. Norepinephrine (NA), meta-octopamine and para-octopamine all show different potencies and / or efficacies in the two different readouts, showing that the two G-proteins modify the interaction of the receptor with the agonist. Source Nanny n Schmiedebeigs Arch Pharmacol. 367 333-41 (2003).

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