Critical Re-evaluation of the Slope Factor of the Operational Model of Agonism Short Title: Slope Factor of the Operational Model of Agonism

Although being a relative term, agonist efficacy is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The operational model of agonism (OMA) has become successful in the determination of agonist efficacies and ranking them. In 1985, Black et al. introduced the slope factor to the OMA to make it more flexible and allow for fitting steep as well as flat concentration-response curves. Functional analysis of OMA demonstrates that the slope factor implemented by Black et al. affects relationships among parameters of the OMA. Fitting of the OMA with Black et al. slope factor to concentration-response curves of experimental as well as theoretical data (homotropic allosteric modulation, substrate inhibition and non-competitive auto-inhibition) resulted in wrong estimates of operational efficacy and affinity. In contrast, fitting of the OMA modified by the Hill coefficient to the same data resulted in correct estimates of operational efficacy and affinity. Therefore OMA modified by the Hill coefficient should be preferred over Black et al. equation for ranking of agonism and subsequent analysis, like quantification of signalling bias, when concentration response curves differ in the slope factor.

On slope factor of the operational model of agonism

Although being a relative term, agonist efficacy is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The operational model of agonism (OMA) has become successful in the determination of agonist efficacies and ranking them. In 1995, Black et al. introduced slope factor to the OMA that makes the OMA more flexible and allows for fitting steep as well as flat concentration-response curves. Here I opinion drawbacks of the slope factor implemented by Black et al. that affects relationships among parameters of the OMA. Instead, I propose the implementation of the Hill coefficient in the OMA that does not affect observed parameters. The OMA modified by the Hill coefficient is more practical in the determination of operational efficacies for agonism ranking and subsequent analysis, like quantification of signalling bias.