Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20 4397
(11) Cavalli, A.; Lattion, A. L.; Hummler, E.; Nenniger, M.; Pe-
drazzini, T.; Aubert, J . F.; Michel, M. C.; Yang, M.; Lembo, G.;
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Deficient of the Alpha1b-Adrenergic Receptor. Proc. Natl. Acad.
Sci. U.S.A. 1997, 94, 11589-11594.
(12) (a) Castillo, E. F.; Lopez, R. M.; Rodriguez-Silverio, J .; Bobadilla,
R. A.; Castillo, C. Alpha 1D-Adrenoceptors Contribute to the
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M. Vascular Alpha(1D)-Adrenoceptors: Are They Related to
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(13) Brioni, J . D.; Brune, M. E.; Buckner, S. A.; Milicic, I.; Daza, A.
V.; Meyer, M. D.; O’Neill, A.; Reinhart, G.; Cox, B.; Altenbach,
R. J .; Holladay, M. W.; Williams, M.; Sullivan, J . P. ABT-866:
A novel R1A-adrenoceptor agonist with R1B/D antagonist proper-
ties. J . Urol. 2001, 165 (Suppl. 5), 34.
(14) Turner, R. M.; Lindell, S. D.; Ley, S. V. A facile route to imidazol-
4-yl anions and their reaction with carbonyl compounds. J . Org.
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(15) Knepper, S. M.; Buckner, S. A.; Brune, M. E.; DeBernardis, J .
F.; Meyer, M. D.; Hancock, A. A. A-61603, A Potent Alpha
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(16) (a) Aboud, R.; Shafii, M.; Docherty, J . R. Investigation of the
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87. (b) Buckner, S. A.; Oheim, K. W.; Morse, P. A.; Knepper, S.
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in rat aorta is mediated by the alpha 1D subtype. Eur. J .
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Chabrier, P. E. Different alpha1-adrenoceptor subtypes mediate
contraction in rabbit aorta and urethra. Eur. J . Pharmacol.
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than the highly R1A selective agonist 2, as well as
midodrine and 4, two agents that have been clinically
tested for the treatment of stress incontinence.
Ack n ow led gm en t. We thank William Carroll for
his critical assessment of this manuscript and for his
scientific advice.
Su p p or tin g In for m a tion Ava ila ble: Figure showing
pressor effect of 1. This material is available free of charge
Refer en ces
(1) (a) Altenbach, R. J .; Khilevich, A.; Meyer, M. D.; Buckner, S.
A.; Milicic, I. V.; Daza, A. V.; Brune, M.; O’Neill, A.; Cain, J . C.;
Nakane, M.; Brioni, J .; Holladay, M. W.; Sullivan, J . P. ABT-
866, a Novel R1-Adrenoceptor Ligand with an Enhanced in Vitro
and in Vivo Profile Relative to Phenylpropanolamine (PPA) and
Midodrine. Presented at the 220th ACS National Meeting,
Washington, DC, August 20-24, 2000; Paper Medi 294. (b)
Buckner, S. A.; Milicic, I.; Daza, A. V.; Meyer, M. D.; Altenbach,
R. J .; Williams, M.; Sullivan, J . P.; Brioni, J . D. ABT-866, a novel
R
1A-adrenoceptor agonist with antagonist properties at the R1B
-
and R1D-adrenoceptor subtypes. Eur. J . Pharmacol., in press.
(2) Anderson, K. E. Pharmacology of Lower Urinary Tract Smooth
Muscles and Penile Erectile Tissues. Pharmacol. Rev. 1993, 45,
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(3) (a) J onas, D. Treatment of Female Stress Incontinence with
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(17) Brune, M. E.; O’Neill, A. B.; Gauvin, D. M.; Katwala, S. P.;
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Comparison of alpha1-adrenoceptor agonists in canine urethral
pressure profilometry and abdominal leak point pressure models.
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(18) Measurements were made within 1 min of dosing to alleviate
any PK effects.
(19) See ref 4. The 5 mmHg increase in IUP was chosen as a
minimally therapeutically relevant effect. The mean urethral
closure pressure in a phenylpropanolamine-treated group of 24
women with slight or moderate stress incontinence increased 7
cmH2O (or 5 mmHg) from 48 to 55 cmH2O and resulted in a
significant decrease in leakage episodes from 5 per 24 h to 2
per 24 h.
(4) Collste, L.; Lindskog, M. Phenylpropanolamine in treatment of
female stress urinary incontinence. Double-blind placebo con-
trolled study in 24 patients. Urology 1987, 30, 398-403.
(5) McClellan, K. J .; Wiseman, L. R.; Wilde, M. I. Midodrine. A
Review of its Therapeutic Use in the Management of Orthostatic
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(20) The 20 mmHg increase in MAP was chosen as a consistently
measurable response above the noise of the assay.
(21) Since compound 1 has affinity for both R1- and R2-adrenoceptors,
the possibility that the MAP effects of compound 1 may in part
be due to activation of R2-adrenoceptors was evaluated. In
binding studies, the affinity of compound 1 for the R2a (human
clone), R2B (neonatal rat lung), and R2c (human clone) adreno-
ceptor subtypes was 171, 973, and 213 nM, respectively. R2-
Adrenoceptors are known to exist postsynaptically in the
periphery, and the R2B-adrenoceptor subtype has been shown
by transgenic models to be responsible for the immediate
hypertensive response to intraveneously administered R2 ago-
nists. See the following references. (a) Lahdesmaki, J .; Sallinen,
J .; MacDonald, E.; Kobilka, B. K.; Fagerholm, V.; Scheinin, M.
Behavioral and neurochemical characterization of alpha(2A)-
adrenergic receptor knockout mice. Neuroscience 2002, 113,
289-299. (b) Hein, L. Transgenic models of alpha 2-adrenergic
receptor subtype function. Rev. Physiol. Biochem. Pharmacol.
2001, 142, 161-185. An in vivo blockade experiment supported
the role of R1- over R2-adrenoceptors in the control of MAP by 1.
The pressor effects in conscious dogs of an iv administered 100
(6) (a) Hieble, J . P.; Bylund, D. B.; Clarke, D. E.; Eikenburg, D. C.;
Langer, S. Z.; Lefkowitz, R. J .; Minneman, K. P.; Ruffolo, R. R.
International Union of Pharmacology. X. Recommendation for
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(8) (a) Rudner, X. L.; Berkowitz, D. E.; Booth, J . V.; Funk, B. L.;
Cozart, K. L.; D’Amico, E. B.; El-Moalem, H.; Page, S. O.;
Richardson, C. D.; Winters, B.; Marucci, L.; Schwinn, D. A.
Subtype specific regulation of human vascular alpha(1)-adren-
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nM/kg dose of
1 were significantly attenuated by the R1
antagonist prazosin (0.3 mg/kg) but not by the R2 antagonist
idazoxan (1 mg/kg).
(22) The following reference describes a study in which the R1A vs
R1B selective agonist methoxamine increased systolic blood
pressure in the absence of a significant rise in maximal urethral
pressure. The authors suggest a limited potential for subtype
selective R1-adrenoceptor agonists in the treatment of stress
incontinence. Radley, S. C.; Chapple, C. R.; Bryan, N. P.; Clarke,
D. E.; Craig, D. A. Effect of methoxamine on maximum urethral
pressure in women with genuine stress incontinence: A placebo-
controlled, double-blind crossover study. Neurourol. Urodyn.
2001, 20, 43-52.
(9) Brune, M. E.; Katwala, S. P.; Milicic, I.; Buckner, S. A.; Ireland,
L. M.; Kerwin, J . F.; Hancock, A. A. Effects of Selective and
Nonselective Alpha-1-Adrenoceptor Antagonists on Intraurethral
and Arterial Pressures in Intact Conscious Dogs. Pharmacology
1996, 53, 356-368.
(10) Hancock, A. A.; Brune, M. E.; Witte, D. G.; Marsh, K. C.;
Katwala, S.; Milicic, I.; Ireland, L. M.; Crowell, D.; Meyer, M.
D.; Kerwin, J . F. Actions of A-131701,
a Novel, Selective
Antagonist for Alpha-1A Compared with Alpha-1B Adrenocep-
tors on Intraurethral and Blood Pressure Responses in Conscious
Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic
Selectivity. J . Pharmacol. Exp. Ther. 1998, 285, 628-642.
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