Effects of N-aralkyl substitution of β-agonists on α- and β-adrenoceptor subtypes: pharmacological studies and binding assays

Abstract

The pharmacological and binding properties of four beta-adrenomimetic drugs with N-alkyl substitutions (isoprenaline, terbutaline, salbutamol and soterenol) were compared with those of four corresponding drugs with N-aralkyl substitutions (protokylol, ME 506, salmefamol and zinterol). BD-40 A, a very powerful beta 2-agonist with a related chemical structure, was also included in this study. The beta 1- and beta 2-activities of these drugs were determined on guinea-pig atria and trachea, their alpha-adrenolytic activity was measured on rat aorta and their affinities (Ki) for alpha 1- and alpha 2-adrenoceptors on rat cortical membranes were assessed using [3H]prazosin and [3H]yohimbine. In this group of beta-agonists, substitution of the N-alkyl by an N-aralkyl group had a variable effect on the beta 2-selectivity whereas alpha-adrenolytic properties were always enhanced. An increase of the affinities (Ki) for both alpha 1- and alpha 2-adrenoceptors was found but the effect was much more pronounced for alpha 1-adrenoceptors. These results indicated that the alpha-adrenolytic activity observed with the N-aralkyl beta-agonists was selective for alpha 1-adrenoceptors.

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

“…Therefore, salbutamol exhibits rapid onset, but the drug diffuses from tissues rapidly causing short duration of effect. The association of formoterol with both receptor and lipid is relatively thermodynamically favourable, allowing fast onset [11,42]. Formoterol is retained in the lipid to be released over an extended period, continually activating the β-adrenoceptor.…”

“…Salmeterol associates predominantly with lipid, and its interaction with the β-adrenoceptor is proposed to be energetically unfavourable causing slow onset of action [18]. In the lower panel, the dissociation of salbutamol and formoterol from the β-adrenoceptor is not impeded (K β2 off), although the affinity of formoterol for the β-adrenoceptor is higher than that of salbutamol [11]. Formoterol is retained with moderate affinity by lipid (K m out) [42].…”

“…Both drugs are highly potent relaxants of human bronchial smooth muscle in vitro (negative log 10 molar concentration for half maximal relaxation±SEM: formoterol 9.6±0.1; salmeterol 7.6±0.2; potency ratio 107 at basal tone) [9]. In addition, they both display a high degree of selectivity for the beta 2 -adrenoceptor subtype [10][11][12][13]. The important differences observed in vitro are that formoterol has a higher intrinsic efficacy [9,12,14] and a faster onset of relaxation than salmeterol [15].…”

Studies on Serotonin (5-HT)3-Receptor Antagonist Effects of Enantiomers of 4,5,6,7-Tetrahydro-lH-Benzimidazole Derivatives

“…The trachea was cut into 7-to 8-mm segments. These were suspended in Krebs solution under a loading tension of 1 g. After the preparations were contracted by 10-'M methacholine, cumulative concentration-relaxant responses to formoterol, a selective X32-adrenoceptor agonist (8,9) were obtained in 7 preparations. In other preparations, responses to formoterol were examined after a 30-min incubation with the antagonist.…”

A dose-response study with formoterol Turbuhaler as maintenance therapy in asthmatic patients

“…It provides good efficacy with b.i.d. dosing [5][6][7][8][9][10], and may, therefore, also have the possibility to improve compliance.…”