Aryl propanolamines: comparison of activity at human β₃ receptors, rat β₃ receptors and rat atrial receptors mediating tachycardia

Abstract

1 The in vitro activity of four aryl propanolamines was compared to two prototypic b 3 receptor agonists, CGP 12177 and CL316243 at the human b 3 receptor, the rat b 3 receptor in the stomach fundus and receptors mediating atrial tachycardia. 2 L-739,574 was the most potent (EC 50 =9 nM) and selective agonist at the human b 3 receptor with high maximal response (74% of the maximal response to isoproterenol). 3 A phenol-biaryl ether analogue possessed modest anity for the human b 3 receptor (EC 50 =246 nM), but was highly ecacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses. 4 These agonists at the human b 3 receptor did not activate the rat b 3 receptor in the rat stomach fundus. In fact, the aryl propanolamines (10 76 M) inhibited CL316243-induced activation of the rat b 3 receptor. Thus, agonist activity at the human b 3 receptor translated into antagonist activity at the rat b 3 receptor. 5 L739,574 and the phenol biaryl ether increased heart rate via b 1 receptors. 6 Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high anity for the human b 3 receptor. Thus, the atrial tachycardic receptor was not identical to the human b 3 receptor. 7 These studies (a) characterized four aryl propanolamines with high anity at the human b 3 receptor, (b) found that they were antagonists at the rat b 3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-b 1 , b 2 or b 3 tachycardic receptor was also unrelated to the human b 3 receptor.

Atrial chronotropic reactivity to catecholamines in neonatal rats: Contribution of β-adrenoceptor subtypes

“…Another novel observation of this study was in regard to the chronotropic responsiveness to the β 3 -adrenoceptor agonist YM178, which, in the submicromolar concentration range, promotes cAMP accumulation attributable to selective stimulation of this subtype (Takasu et al, 2007). Atria from adult rats were unresponsive to YM178, which is in agreement with previous reports that selective β 3 -adrenoceptor stimulation does not affect atrial rate or cAMP production in adult mammals (Tavernier et al, 1992;Cohen et al, 1999;Heubach et al, 2002; but see Sterin-Borda et al, 2006). In neonatal atria, however, although β 3 -adrenoceptor mRNA levels were similar to those in adults, the agonist evoked a significant increase in spontaneous rate.…”

β3‐AR and the vertebrate heart: a comparative view

“…At the same time, in the rat atrium, β 3 ‐ARs stimulation by various agonists was found to be either ineffective (Kaumann & Molenaar ) or tachycardic (Cohen et al . ). Moreover, the cardiac β 3 ‐AR‐dependent intracellular signal pathways are not univocally defined.…”

Tools to study β3-adrenoceptors

“…In contrast to the genes of β 1 -and β 2 -adrenoceptor, the β 3 -adrenoceptor gene contains one or more introns . While the species homologues of the β- adrenoceptor subtypes have great amino acid homology (Table 1), minor differences in amino acid sequence between species homologues of β 3 -adrenoceptors can translate into noticeable differences in ligand recognition patterns (Arch 2002;Cohen et al 1999;Granneman et al 1991;Hutchinson et al 2006;Liggett 1992;Molenaar et al 1997;Tate et al 1991). An important structural difference between the β 3 -and the β 1 -and β 2 -adrenoceptors is the absence of phosphorylation sites for cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) or G-protein-coupled receptor kinase in the short C terminus of the β 3 -adrenoceptor, which is thought to be the basis for its relative resistance to agonist-induced downregulation .…”