Using Esterase Selectivity to Determine the In Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers

Abstract

For disorders of the skin, eyes, ears, and respiratory tract, topical drugs, delivered directly to the target organ, are a therapeutic option. Compared with systemic oral therapy, the benefits of topical treatments include a faster onset of action, circumventing the liver first pass drug metabolism, and reducing systemic side effects. Nevertheless, some systemic absorption still occurs for many topical agents resulting in systemic side effects. One way to prevent these would be to develop drugs that are instantly degraded upon entry into the bloodstream by serum esterases. Because topical β-blockers are used in glaucoma and infantile hemeangioma and cause systemic side effects, the β-adrenoceptor system was used to test this hypothesis. Purified liver esterase reduced the apparent affinity of esmolol, an ester-containing β-blocker used in clinical emergencies, for the human β-adrenoceptors in a concentration and time-dependent manner. However, purified serum esterase had no effect on esmolol. Novel ester-containing β-blockers were synthesized and several were sensitive to both liver and serum esterases. Despite good in vitro affinity, one such compound, methyl 2-(3-chloro-4-(3-((2-(3-(3-chlorophenyl)­ureido)­ethyl)­amino)-2-hydroxypropoxy)­phenyl)­acetate, had no effect on heart rate when injected intravenously into rats, even at 10 times the equipotent dose of esmolol and betaxolol that caused short and sustained reductions in heart rate, respectively. Thus, ester-based drugs, sensitive to serum esterases, offer a mechanism for developing topical agents that are truly devoid of systemic side effects. Furthermore, differential susceptibility to liver and serum esterases degradation may also allow the duration of systemic availability for other drugs to be fine-tuned.

The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Humanβ1-Adrenoceptor

“…For the other three β1-AR compounds, betaxolol, bisoprolol and esmolol (which are neutral antagonists in these cells; Baker et al, 2011;Baker et al, 2017;Baker et al, 2020;Mistry et al, 2013), their moderate β1-selectivity was not affected at the β1-I118H, nor the β2-H93I…”

“…Other β-ligands with moderate β1-selectivity were then examined. ICI89406 (another β1partial agonist, Mistry et al, 2013), and betaxolol, bisoprolol and esmolol (β-antagonists without efficacy in these cells; Baker et al, 2011;Baker et al, 2017;Baker et al, 2020;Mistry et al, 2013) had β1-WT (vs β2-WT) binding affinity selectivities of 81-, 14-, 30-and 13-fold, respectively (Table 2, Figure 3). When ICI89406 was examined in the TM2 constructs, it also had reduced affinity in the β1-I118H, compared to β1-WT.…”