Why are long-acting beta-adrenoceptor agonists long-acting?

Abstract

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

“…Therefore, the hypothesis for the persistence and reassertion profile of vilanterol is more than likely the same as that arrived at in previous studies in terms of the "microkinetic" model (Anderson et al, 1994) describing a highly lipophilic molecule partitioning into cell membrane and forming depots of drug [the calculated log P value for vilanterol (3.2) is comparable to that of salmeterol (3.1), calculated by Daylight Chemical Information Systems Inc., Laguna Niguel, CA]. The debate around the mechanism for the long clinical duration of action exhibited by inhaled b 2 -AR agonists has been ongoing since the discovery and clinical use of salmeterol and formoterol in the early 1990s.…”

Quantitative autoradiographic studies of relaxin binding in rat atria, uterus and cerebral cortex: characterization and effects of oestrogen treatment

“…The ®rst hypothesis was con®rmed in dissociation studies, where more than 50% of labelled relaxin still remained in the tissue after 4 h of washing, and in functional studies where the chronotropic and inotropic responses to relaxin persisted even after 6 h of washing (Tan et al, 1998). The second hypothesis has been described in studies on interactions of b 2 -agonists with b 2 -adrenoceptors (see review by Anderson et al, 1994 andLiggett &Green, 1997) but yet to be veri®ed for the relaxin receptor.…”

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

“…At lower levels, constant partitioning/exchange of drug molecules between the membrane and the surrounding aqueous medium may allow the membrane to act as a repository/reservoir and, in this manner, prolong the exposure of the targets to a sufficiently high concentration of drug. In this respect, the 'diffusion microkinetic' model [23,24] linked the longlasting relaxation of airway smooth muscle in response to hydrophobic β 2 -adrenoceptor agonists, such as formoterol and salmeterol, to their slow release from the membrane, regardless of how the receptor is finally approached (Figure 1). Indeed, whereas the released formoterol molecules were proposed to reach the receptor via classical three-dimensional (3D) diffusion within the aqueous phase, the more lipophilic salmeterol molecules were proposed to reach the receptor directly by two-dimensional (2D) diffusion within the plane of the membrane.…”