Tracheal Relaxing Effects and β2-Selectivity of TA-2005, a Newly Developed Bronchodilating Agent, in Isolated Guinea Pig Tissues

Abstract

ABSTRACT-Tracheal relaxing effects and /32-selectivity of TA-2005 were investi gated by functional experiments and radioligand binding assay in guinea pigs in com parison with those of other ,Q-agonists, isoproterenol, procaterol, formoterol and sal butamol. The relaxing activity of TA-2005 on histamine-induced contraction in the isolated trachea was most potent among the five agonists, and it was blocked by a 82 selective antagonist (ICI 118,551) but not by a /3,-selective antagonist (bisoprolol). The potency of the relaxing effect was in the order of TA-2005 (pD-, = 9.79) > for moterol > procaterol > isoproterenol > salbutamol. The positive chronotropic effect of TA-2005 was similar to that of isoproterenol; and it was more potent than those of formoterol, procaterol and salbutamol in the isolated atria. The selectivity for tracheal muscle to atria of these agonists were in the order of procaterol > formoterol > TA 2005 > salbutamol >> isoproterenol. A radioligand binding experiment using guinea pig lung and cardiac ventricle as ,82 and 81-adrenoceptor sources, respectively, has also demonstrated that TA-2005 possesses extremely high affinity (IC50 = 1.04 nM) and selectivity (38-fold) to X32-adrenoceptors. By addition of GTP, the competition curve of [1251 ]iodocyanopindolol shifted rightward, indicating the agonist property. These results confirmed that TA-2005 is a highly 82-selective agonist that exerts a po tent tracheal relaxing effect.

Pharmacology and Therapeutics of Bronchodilators

“…Moreover, it displays a fast onset and long duration of activity under both in vitro and in vivo experimental conditions (Kikkawa et al, 1991(Kikkawa et al, , 1994Voss et al, 1992). It is noteworthy that the persistence of action of carmoterol at human recombinant ␤ 2 -ARs is similar to that of salmeterol, and longer than that of indacaterol, which is longer than that of formoterol (Summerhill et al, 2008).…”

“…Carmoterol. Carmoterol (CHF 4226, TA 2005), a pure R,R-isomer, is a noncatechol ␤ 2 -agonist with a pmethoxyphenyl group on the amine side chain and a 8-hydroxyl group on the carbostyril aromatic ring (Kikkawa et al, 1991), possesses structural elements from both formoterol and procaterol, and binds very firmly to ␤ 2 -ARs (Voss et al, 1992), a property shared by some other agonists that, like carmoterol, are based on a carbostyril skeleton (Standifer et al, 1989). In studies employing chimeric ␤ 2 -ARs, the methoxyphenyl group in carmoterol has been found to be critical to the ␤ 2 -AR selectivity of the molecule (Kikkawa et al, 1998).…”

Efficacy and safety of long-acting beta-2-agonists

“…Прием всех исследованных дозировок вилантерола сопровождался низкой частотой побоч ных эффектов [39]. Кармотерол -чистый R,R изомер -некатехолами новый агонист β 2 АР с р метоксифенильной груп пой на аминовой боковой цепи и 8 гидроксильной группой на карбостириловом ароматическом коль це [40]. Он несет в своем строении структурные эле менты как формотерола, так и прокатерола, и очень Новое о лекарственных препаратах прочно связывается с β2 АР [41].…”

Emerging inhaled bronchodilators: an update

“…Carmoterol (CHF 4226; TA 2005), a noncatechol b 2 -adrenoceptor agonist with a p-methoxyphenyl group on the amino side chain and a 8-hydroxyl group on the carbostyril aromatic ring [27], possessing structural elements from both formoterol and procaterol, binds very firmly to the b 2 -adrenoceptor [28]. Carmoterol displays a fast onset and long duration of activity under both in vitro and in vivo experimental conditions [27][28][29].…”

“…Carmoterol displays a fast onset and long duration of activity under both in vitro and in vivo experimental conditions [27][28][29]. Carmoterol is in development by Chiesi Farmaceutici (Parma, Italy), under license from Tanabe Seiyaku Co. (Saitama, Japan).…”