Interactions of a novel catecholamine, GP-2-128, with adrenoceptors

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GP-2-128 is a novel catecholamine designed for transdermal iontophoretic delivery in patients with limited mobility to prevent deconditioning and muscular wasting. We characterized the interactions of this agent with α- and β-adrenoceptors in vitro. In electrically stimulated rat left atria, GP- 2-128 produced a concentration-dependent increase in contractile force. pD2 values for GP-2-128, isoproterenol (ISO), and dobutamine (DOB) were 10.6 ± 0.12, 8.55 ± 0.02, and 7.0 ± 0.20, respectively. Metoprolol caused a shift in the concentration-effect curves for the three agonists. In spontaneously beating rat right atria, pD2 values of GP-2-128, ISO, and DOB are 10.4 ± 0.24, 8.82 ± 0.18, and 6.92 ± 0.18, respectively. The affinity constant (K(A)) of GP-2-128, ISO, and DOB for cardiac β1-adrenoceptors was determined by competition binding assays to be 8.09, 6.04 and 4.49, respectively. In guinea pig trachea precontracted with histamine. GP-2-128 and ISO produced a concentration-dependent relaxation. pD2 values were 10.0 ± 0.1 and 8.2 ± 0.1, respectively. DOB was more potent than GP-2-128 in contracting isolated rat aortic rings (α1 effect) and in displacing [3H]rauwolscine (α2 effect). We also studied the interactions of GP-2-128 and ISO with the atypical β-adrenoceptors (β3) in guinea pig ilea and rat and hamster adipocytes. Both agents inhibited twitches produced by transmural nerve stimulation in the presence of 1010 M nadolol. The EC30 for GP-2- 128 and ISO at this atypical receptor site were 4.25 x 10-10 and 5.05 x 10-8 M, respectively. Nadolol blocked β3-adrenoceptors with an estimated pA2 value range from 4.76 to 4.8. In rat white adipocytes, GP-2-128 stimulated glycerol release. The order of potency of the agents tested was GP-2-128 > BRL-37344 > ISO, whereas in hamster brown adipocytes, the order was GP-2-128 > ISO > BRL-37344. GP-2-128 is a novel catecholamine with higher potency and efficacy than ISO and DOB in increasing cardiac contractility by stimulating cardiac β-adrenoceptors. GP-2-128 does not stimulate α- adrenoceptors at concentrations high enough to activate the β-adrenoceptors but does stimulate β-adrenoceptors, which may have a role in metabolic activity.

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