Pharmacological properties of A-204176, a novel and selective alpha1A adrenergic agonist, in in vitro and in vivo models of urethral function.
A-204176 (N-[5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide) is a potent and selective alpha1A adrenoceptor agonist that binds with 17-fold and 9-fold greater affinity to the alpha1A (Ki=176 nM) than the alpha1b and alpha1d subtypes, respectively. In functional studies A-204176 is potent (pD2=6.4) and efficacious (83% of maximum control phenylephrine response) at rabbit urethra alpha1A receptors, with weaker potency and greatly reduced efficacy at rat spleen alpha1B (pD2=5.3, 11%) and rat aorta alpha1D (pD2=4.4, 10%) subtypes. In anesthetized female dogs, A-204176 is more potent than the non-selective alpha1 adrenoceptor agonist phenylpropanolamine (PPA) to increase measures of urethral tone and is more efficacious to increase pressure in the proximal region of the urethra. Significant increases on parameters of the urethral pressure profilometry were induced at 100 and 300 nmol/kg, i.v., by A-204176 and PPA, respectively. A-204176 was more potent than PPA to increase the abdominal pressure required to produce leakage. In the simultaneous measurement of intraurethral pressure and mean arterial blood pressure, A-204176 displays enhanced urethral selectivity relative to PPA. However, despite its selectivity for alpha1A versus alpha1B and alpha1D adrenoceptors in vitro, A-204176 did not display the degree of urethral selectivity in vivo that would have been expected. The observed effect of A-204176 on blood pressure may be due to the presence of extra-synaptic alpha1A adrenoceptors in the vasculature or to activation of spinal and supraspinal alpha1A adrenoceptors. These data indicate that A-204176 may represent a useful pharmacological tool to investigate the functional role of the alpha1A adrenoceptor in the urethra and to elucidate the lack of uroselectivity observed in vivo.
O'Neill
A B
AB
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA. alyssa.b.oneill@abbott.com
Buckner
S A
SA
Brune
M E
ME
Milicic
I
I
Daza
A V
AV
Gauvin
D M
DM
Altenbach
R J
RJ
Meyer
M D
MD
Williams
M
M
Sullivan
J P
JP
Brioni
J D
JD
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010665:Phenylpropanolamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011312:Pressure; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects* / Q000502:physiology; D014546:Urinary Catheterization; D014563:Urodynamics
D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; C445279:N-(5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl)methanesulfonamide; D013764:Tetrahydronaphthalenes; D010665:Phenylpropanolamine; D011224:Prazosin