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Abstract: Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with α1 adrenergic receptor antagonists. Unfortunately, currently marketed α1 blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an α1a/1d subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective α1a/1d ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human α1-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both α1a, and α1d subtypes, with 14- to 47-fold selectivity versus the α1b subtype and >15-fold selectivity versus dopamine D2. [Copyright &y& Elsevier]

Abstract: Although α1 adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by CV-related side-effects that are caused by the subtype non-selective nature of the current drugs. To overcome this problem, it was hypothesized that a α1a/1d subtype selective antagonist would bring more benefit for the therapy of BPH/LUTS. In developing such selective α1a/1d ligands, a series of (phenylpiperidinyl)cyclohexylsulfonamides has been synthesized and evaluated for binding to three cloned human α1-adrenergic receptor subtypes. Many compounds showed equal affinity for both α1a and α1d subtypes with good selectivity versus the α1b subtype. [Copyright &y& Elsevier]

Abstract: Subtype-selective α-1a and/or α-1d adrenergic receptor antagonists may be useful for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) with fewer adverse effects than non-selective drugs. A series of 1-arylpiperazinyl-4-cyclohexylamine derived isoindole-1,3-diones has been synthesized, displaying in vitro α1a and α1d binding affinity K i values in the range of 0.09–38nM with K i(α1b)/K i(α1a) and K i(α1b)/K i(α1d) selectivity ratios up to 3607-fold. [Copyright &y& Elsevier]

An α1a-adrenoceptor-selective antagonist has the potential to be a new benign prostatic hyperplasia drug with reduced side-effects. Modification of the non-selective antagonist BE2254 led to the development of a series of tetralin analogs. Evaluation of these compounds in cloned human α1-adrenoceptors resulted in the discovery of an analog that showed selectivity toward the human α1a-adrenergic receptor subtype. The compound also showed moderate potency to block human prostate muscle contraction. [ABSTRACT FROM AUTHOR]