Pharmacological properties of A-204176, a novel and selective alpha(1A) adrenergic agonist, in in vitro and in vivo models of urethral function

A-204176 (N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methane sulfonamide) is a potent and selective alpha (1A) adrenoceptor agonist that binds with 17-fold and 9-fold greater affinity to the alpha (1A) (Ki=176 n M) than the alpha (1b) and alpha (1d) subtypes, respectively. In functional studies A-204176 is potent (pD(2)=6.4) and efficacious (83% of maximum con trol phenylephrine response) at rabbit urethra alpha (1A) receptors, with w eaker potency and greatly reduced efficacy at rat spleen alpha (1B) (pD(2)= 5.3, 11%) and rat aorta alpha (1D) (pD(2)=4.4, 10%) subtypes. In anesthetiz ed female dogs, A-204176 is more potent than the non-selective alpha (1) ad renoceptor agonist phenylpropanolamine (PPA) to increase measures of urethr al tone and is more efficacious to increase pressure in the proximal region of the urethra. Significant increases on parameters of the urethral pressu re 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 abdomi nal pressure required to produce leakage. In the simultaneous measurement o f intraurethral pressure and mean arterial blood pressure, A-204176 display s enhanced urethral selectivity relative to PPA. However, despite its selec tivity for alpha (1A) versus alpha (1B) and alpha (1D) adrenoceptors in vit ro, A-204176 did not display the degree of urethral selectivity in vivo tha t would have been expected. The observed effect of A-204176 on blood pressu re may be due to the presence of extra-synaptic alpha (1A) adrenoceptors in the vasculature or to activation of spinal and supraspinal alpha (1A) adre noceptors. These data indicate that A-204176 may represent a useful pharmac ological tool to investigate the functional role of the alpha (1A) adrenoce ptor in the urethra and to elucidate the lack of uroselectivity observed in vivo. (C) 2001 Elsevier Science Inc. All rights reserved.