Partial agonism

Interpretation of Partial Agonism in Terms of Events at Individual Receptors... 

Some of the most revealing studies of partial agonism (including Stephenson s seminal work) have been done with tissues in which G-proteins (see Chapters 2 and 7) provide the link between receptor activation and initiation of the response. In contrast to the situation with fast receptors with intrinsic ion channels (see above), it is not yet possible to observe the activity of individual G-protein-coupled receptors (with the potential exception of some that are linked to potassium channels) however, enough is known to show that the mechanisms are complex. The interpretation of differences in efficacy for agonists acting at such receptors is correspondingly less certain. 

However, as already discussed, it has now become clear that the occupancy and activation of a receptor by an agonist are not equivalent hence, Stephenson s use of the Hill-Langmuir equation to relate agonist concentration to receptor occupancy in Eq. (1.27) is an oversimplification. Our final task in this account of partial agonism is to reexamine Stephenson s formulation of efficacy, and the results of experiments based on it, in the light of the new knowledge about how receptors function. 

Nikolaev, V. O., Hoffmann, C., Bunemann, M., Lohse, M. J. and Vilardaga, J. P. (2006). Molecular basis of partial agonism at the neurotransmitter alpha2A-adrenergic receptor and Gi-protein heterotrimer. J. Biol. Chem. 281, 24506-11. 

TRANSFORMATION OF PARTIAL AGONISM INTO ANTAGONISM IN 4-PIOL ANALOGS... 

Holst, B., Elling, C. E., and Schwartz, T. W. (2000) Partial agonism through a zinc-ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor. Mol. Pharmacol. 58, 263-270. 

Ebersole, B. J., Visiers, I., Weinstein, H., and Sealfon, S. (2003) Molecular basis of partial agonism orientation of indolamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy. Mol. Pharmacol. 63, 36—43. 

However, the p-receptor at which such partial agonism can be shown appears to be atypical (P3 or P4 subtype). Whether ISA confers a therapeutic advantage on a p-blocker remains an open question. 

These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. The fact that aripiprazole shows partial agonism at D2 and 5-HT1A receptors in preclinical studies suggests that the proportions of several receptors in their various affinity states may prove clinically important. 

The structural manipulation at different positions of adenosine provided a wide number of ligands at the A3 AR exerting different levels of potency, selectivity, and intrinsic efficacy. The exact combination of modifications showed to affect the balance between full agonism, partial agonism and antagonism (Joshi and Jacobson 2005). 

Some 2 and 3 -fluoro analogues of Cl-IB-MECA have been investigated as A3 AR ligands (Lim et al. 2003). While the introduction of a fluorine atom at the 2 -position compromised both A3 AR binding and activation, the 3 -fluoro substitution generally resulted in partial agonism. Compound 27 is one of the few ligands... 

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