Efficacy agonists

In some cases, the stimulus-response characteristics of a system can be manipulated to provide a means to compare maximal responses of agonists (efficacy). 

Agonists can produce complex binding profiles due to the formation of different protein species (i.e., ternary complexes with G-proteins). The extent of this phenomenon is related to the magnitude of agonist efficacy and can be used to quantify efficacy. 

Operational model, devised and published by James Black and Paul Leff (Proc. R. Soc. Lond. Biol. 220,141-162, 1983), this model uses experimental observation to describe the production of a physiological response by an agonist in general terms. It defines affinity and the ability of a drug to induce a response as a value of x, which is a term describing the system (receptor density and efficiency of the cell to convert an activated receptor stimulus into a response) and the agonist (efficacy). It has provided a major advance in the description of functional effects of drugs see Chapter 3.6 for further discussion. 

Stereospecificity suggests that there are three geometrically distinct determinants of the structure which are important to agonist efficacy and potency, whereas previous models only utilized two features. A hydrophobic pocket may also be important 20) this could be supplied by the [4.2.1]nonene structure. Our intentions are to explore the domains of the agonist molecule to determine the specific determinants of agonist activity. 

Davies, M. A., Setola, V., Strachan, R. T, et al. (2006) Pharmacologic analysis of non-syn-onymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics. J. 6, 42-51. 

Christ GJ, Spray DC, El-Sabban M, Moore LK, Brink PR Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation ofvascular tone. Cite Res 1996 79 631-646. Christ GJ, Zao W, Moss J, Gondre CM, Roy C, Brink PR, Spray DC Gap junctions modulate tissue contractility and al-adrenergic agonist efficacy in isolated rat aorta. J Pharmacol Exp Ther 1993 266 1054-1065. 

Fig. 7.15 Modifications of the 5 -uronamide moiety of known ARs agonists efficacious in promoting antagonistic behaviour...

Chidiac P, Nouet S, Bouvier M. Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor. Mol Pharmacol 1996 50 662-669. 

Beyond delta agonist selectivity and mu or delta receptor availability in vivo, the observation of decreased delta agonist efficacy in mice lacking mu receptors could also be explained by functional cooperation of mu and delta receptors. It is likely that some delta receptor-mediated effects require mu receptors for full activity (see Rothman and Xu, Chap. 21). Where in the brain, and whether this occurs between receptors located in the same neurons or on different neurons within neural circuits, remains to be determined. 

Although in the tests that had been applied to MC-CAM, buprenorphine showed close similarity, there were some notable differences. In particular MC-CAM s opioid antagonist effects were MOR-selective whereas buprenorphine also had KOR and DOR antagonism. In rhesus monkeys MC-CAM also appeared to have greater MOR agonist efficacy than buprenorphine in antinociceptive assays and, at least initially, unlike buprenorphine it suppressed morphine abstinence. Based on these similarities to, and differences from, buprenorphine, the ligand deserves consideration as a treatment for opioid abuse. 

Among the 14-pyridylacryloylaminocodeinones and morphinones there was not a consistent relationship between 2 -, 3 - and 4 -isomers in terms of MOR agonist efficacy in the 17-methyldihydrocodeinones (52a-54a) the relationship was 2 > 3 > 4, whereas with the corresponding dihydromorphinones (52b-54b) the reverse was true. It was therefore difficult to draw comparisons with the... 

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