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Terazosin and its enantiomers, antagonists of alpha 1-adrenoceptors, were studied in radioligand binding and functional assays to determine relative potencies at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro. The racemic compound and its enantiomers showed high and apparently equal affinity for subtypes of alpha 1-adrenoceptors with Kl values in the low nanomolar range, and showed potent antagonism of alpha 1-adrenoceptors in isolated tissues, with the enantiomers approximately equipotent to the racemate at each alpha 1-adrenoceptor subtype. At alpha 2b sites, R(+) terazosin bound less potently than either the S(-) enantiomer or racemate. R(+) terazosin was also less potent than the S(-) enantiomer or the racemate at rat atrial alpha 2B receptors. These agents were not significantly different in their potencies at alpha 2a or alpha 2A sites. Since the high affinity for alpha 2B sites of quinazoline-type alpha-adrenoceptor antagonists has been used to differentiate alpha 2-adrenoceptor subtypes, the low affinity of R(+) terazosin for these sites was unexpected. Because terazosin or its enantiomers are approximately equipotent at alpha 1-adrenoceptor subtypes, the lower potency of R(+) terazosin at alpha 2B receptors indicates a somewhat greater selectivity for alpha 1-compared to alpha 2B adrenoceptor subtypes. The possible pharmacological significance of this observation is discussed.

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with ␣ 1 -adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at ␣ 1A -and ␣ 1D -(compared with ␣ 1B -) adrenoceptors were evaluated that would block lower urinary tract ␣ 1 -adrenoceptors in preference to cardiovascular ␣ 1B -adrenoceptors. 9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydroABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR). Fiduxosin had higher affinity for cloned human ␣ 1a -(0.16 nM) and ␣ 1d -adrenoceptors (0.92 nM) in radioligand binding studies compared with ␣ 1b -adrenoceptors (25 nM) or in isolated tissue bioassays [pA 2 values of 8.5-9.6 for ␣ 1A -receptors in rat vas deferens or canine prostate strips, 8.9 at ␣ 1D -adrenoceptors (rat aorta), compared with 7.1 at ␣ 1B -adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative ␣ 1L -adrenoceptors in the rabbit urethra (pA 2 value of 7.58). Fiduxosin blocked epinephrineinduced increases in canine IUP (pseudo-pA 2 value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC 0360 min) for the hypotensive response was dose related with a log index value for fiduxosin of 5.23, indicating a selectivity of 770-fold comparing IUP to MAP effects. Preferential antagonism of ␣ 1A -and ␣ 1D -versus ␣ 1B -adrenoceptors in vitro, blockade of putative ␣ 1L -sites in vitro, and selective effects on lower urinary tract function versus blood pressure in vivo by fiduxosin suggest the potential utility of this compound for the treatment of BPH.Benign prostatic hyperplasia (BPH), a change in the size, composition, and function of the prostate gland, leads to obstruction of the bladder and urethra in middle-aged and elderly males. The enlarged prostate is composed of glandular epithelium and a large stromal component containing mostly smooth muscle (Shapiro and Lepor, 1991). Although the term BPH might suggest that symptoms arise exclusively from increased organ size causing mechanical obstruction of urine flow, no correlation between prostate size and symptom severity has been shown (Shapiro and Lepor, 1995). Rather, an important "dynamic" component to BPH results from alterations in sympathetic control of prostatic smooth muscle tone, mediated primarily through ␣ 1 -adrenoceptor mecha- ; DMSO, dimethyl sulfoxide; PE, phenylephrine; IUP, intraurethral pressure; EPI, epinephrine; SHR, spontaneously hypertensive rats; MAP, mean arterial blood pressure; AUC, area under the curve; pED 50 , negative logarithm of the molar dose of compound required to elicit a reduction in blood pressure for 60 min to a point midway between hypertensive and normotensive; ANOVA, analysis of variance; K i , inhibition constant as a measure of drug affinity for a receptor, equivalent to the concentra...

In this study, we used a novel conscious dog model to evaluate the uroselectivity of selected α₁-antagonists either approved for human use or in clinical development for the treatment of symptomatic benign prostatic hyperplasia (BPH) and compared those results to their in vitro binding and functional affinities at α_1A, α_1B, and α_1D receptor subtypes. Conscious dogs were instrumented acutely with a balloon catheter for the measurement of changes in prostatic intraurethral pressure (IUP) and chronically with implantable telemetry devices for the measurement of arterial pressure. The pressor effects of the α₁-agonist phenylephrine (PE) on IUP and mean arterial pressure (MAP) were compared before and at various time points after oral doses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SB 216469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; however, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2739 at each dose always blocked IUP to a greater extent than MAP. While the in vivo uroselectivity of these agents was predicted by radioligand binding and in vitro functional selectivity for the α_1A subtype over α_1B and α_1D subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also depend upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of uroselectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practice.