Bank, She eld, ST10 2TN and 4 8 Palace Garden, Royston, Hertfordshire, S68 5AD1 It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the a 1A -adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. 2 The present study describes the a 1 -adrenoceptor (a 1 -AR) subtype selectivities of two novel a 1 -AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned a 1A -, a 1B -and a 1D -AR showed nanomolar a nity and signi®cant a 1A -AR subtype selectivity for both Ro 70-0004 (pK i 8.9: 60 and 50 fold selectivity) and RS-100329 (pK i 9.6: 126 and 50 fold selectivity) over the a 1B -and a 1D -AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. 3 Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA 2 8.8 and 8.9), RS-100329 (pA 2 9.2 and 9.2), tamsulosin (pA 2 10.4 and 9.8) and prazosin (pA 2 8.7 and 8.3 respectively). A nity estimates for tamsulosin and prazosin in antagonizing a 1 -AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA 2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). 4 The a 1A -AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a`uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.
Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
Attachment of the chiral formamidine moiety to 6-methoxy-l,2,3,4-tetrahydroisoquinoline afforded the key chiral, nonracemic precursor 8, upon which the azasteroid skeleton was constructed. Asymmetric alkylation with a-halo esters or &halo ethers gave 16 and 22, respectively, in high ee's. -Cyclization, following enamine formation with cyclopentanedione or cyclopentanone, led to the chiral steroidal skeletons 6 and 5, respectively. The fiial stereocenters, leading to 8-azaestrone 4 with unnatural absolute configuration (antipodal), were accomplished by intramolecular alkylation of (+)-6b and subsequent reduction and ether cleavage. For the 12-oxoeteroid 3, the methyl at C-13 WBB inserted by initial conjugate reduction of the enone 5 with a copper hydride reagent (Stryker method) requiring the presence of a silyl chloride affording 21. The addition of methyl iodide to C-13 occurred after transforming the triethylsilyl enol ether, 21, to ita lithium enolate. Stereochemical assignments for both azasteroids 3 and 4 were confirmed by spectroscopic means including circular dichroism curves.The steroids continue to be actively studied, particularly with regard to modulating gene expressions.' Azasteroids such as 1 have been utilized to evaluate oncogenic events HO & V I 0 4 i y 2 4 c 1 NEt, 4 3 1 936 98 88 d 97 93 91 39 C1,C-cc1, 'A solution of 12, at -78 "C, was added to a solution of the electrophile at -110 O C . b A suspension of 1.2 equiv of KH was present during the addition of 12 to the a-halo ester. 'An equal mixture of 8 and 14 was obtained. d R = NHNHz was the only product.in THF.' This was followed by treatment with dimethylformamide-dimethyl acetal to afford the (di-methy1amino)formamidine alcohol (crude yield, quantitative) and ita subsequent transformation to 11 with potassium hydride and methyl iodide. The overall transformation from tert-leucine to 11 was performed in 81-89% yield.The next task en route to reaching the azasteroids was the acetylmethylation of 8. To this end, a series of a-halo esters and amides were examined by introducing them to the 1-lithio formamidine 12. The latter was generated from 8 using n-butyllithium in THF at -78 "C after 30 min. Of
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