ABT-866, a novel alpha(1A)-adrenoceptor agonist with antagonist properties at the alpha(1B)- and alpha(1D)-adrenoceptor subtypes.
N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide, maleate (ABT-866) is a novel alpha(1)-adrenoceptor agent with mixed pharmacological properties in vitro. Compared to phenylephrine, ABT-866 demonstrates intrinsic activity at the alpha(1A)-adrenoceptor subtype present in the rabbit urethra (pD(2) = 6.22, with 80% of the phenylephrine response), reduced intrinsic activity at the alpha(1B)-adrenoceptor subtype in the rat spleen (pD(2)= 6.16, with 11% of the phenylephrine response), and no intrinsic activity at the rat aorta alpha(1D)-adrenoceptor subtype. ABT-866 also demonstrated antagonism at the rat spleen alpha(1B)-adrenoceptor (pA(2) = 5.39 +/- 0.08, slope = 1.20 +/- 0.12), and the rat aorta alpha(1D)-adrenoceptor (pA(2)= 6.18 +/- 0.09, slope = 0.96 +/- 0.13). This is in contrast to the weak non-selective activity seen with the alpha(1)-adrenoceptor agonist, phenylpropanolamine (2-amino-1-phenyl-1-propanol hydrochloride), and the alpha(1A/D)-adrenoceptor selective agonist 1-(2',5'-dimethoxyphenyl)-2-aminoethanol hydrochloride (ST-1059), the active metabolite of midodrine, that has been used clinically for the treatment of stress urinary incontinence. This study identifies a unique agent that may prove to be a valuable in vivo tool in testing the hypothesis that the alpha(1A)-adrenoceptor can be stimulated to contract the smooth muscle present in the urethra without evoking blood pressure elevations presumably caused by alpha(1B)- and alpha(1D)-adrenoceptor subtype involvements in the vasculature.
Buckner
Steven A
SA
Neuroscience Research, Global Pharmaceutical Research and Development, Department R4ND, Bldg AP9A, Third Floor, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6125, USA.
Milicic
Ivan
I
Daza
Anthony V
AV
Meyer
Michael D
MD
Altenbach
Robert J
RJ
Williams
Michael
M
Sullivan
James P
JP
Brioni
Jorge D
JD
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D013154:Spleen / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D014649:Vas Deferens / Q000187:drug effects
C466636:ABT 866; C547714:Adra1a protein, mouse; C547715:Adra1a protein, rat; C547717:Adra1b protein, mouse; C547718:Adra1b protein, rat; C547720:Adra1d protein, mouse; C547721:Adra1d protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides