Interactions of a novel catecholamine, GP-2-128, with adrenoceptors.
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 alpha- and beta-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 (KA) of GP-2-128, ISO, and DOB for cardiac beta 1-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 (alpha 1 effect) and in displacing [3H]rauwolscine (alpha 2 effect). We also studied the interactions of GP-2-128 and ISO with the atypical beta-adrenoceptors (beta 3) in guinea pig ilea and rat and hamster adipocytes. Both agents inhibited twitches produced by transmural nerve stimulation in the presence of 10(-5) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Abou-Mohamed
G
G
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912.
Caldwell
R W
RW
Carrier
G O
GO
Elmazar
M M
MM
Tuttle
R R
RR
D017667:Adipocytes / Q000187:drug effects; D018674:Adrenergic Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002395:Catecholamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D004280:Dobutamine / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
D018674:Adrenergic Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D001549:Benzamides; D002317:Cardiovascular Agents; D002395:Catecholamines; D011941:Receptors, Adrenergic; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C087657:1-(3,4-dihydroxyphenyl)-2-(3-(4-carbamylphenyl)-1-methylpropylamino)ethanol; D004280:Dobutamine; D007545:Isoproterenol