1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans Their overall post-junctional function in the lower urinary tract remains largely unclear 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment

/pdf/a1-a2-and-b-adrenoceptors-in-the-urinary-bladder-urethra-and-141o0muabo.pdf

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

In search of a uroselective α1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,1 this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the α1A/α1B selectivity of these compounds were identified. In vitro functional assays for the α1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole α1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia

An enantioselective [4 + 1] annulation/rearrangement cascade of stable sulfur ylides and nitroolefins has been developed through an efficient axial-to-central chirality transfer with the use of a chiral BINOL-derived sulfide as a reliable stereocontroller. It can provide pharmaceutically and synthetically important oxazolidinones in high stereoselectivities (up to 96:4 e.r. and >95:5 d.r.). Moreover, this strategy was also successfully applied to the asymmetric [4 + 1]/[3 + 2] cycloaddition cascade of sulfur ylides with alkene-tethered nitroolefins, and the corresponding enantioenriched fused heterocycles (up to 87:13 e.r. and >95:5 d.r.) were obtained in good to excellent yields (54–95% yields).

Enantioselective Cascade Reactions of Stable Sulfur Ylides and Nitroolefins through an Axial-to-Central Chirality Transfer Strategy

α1-Adrenoceptors have been identified and characterized extensively by functional, radioligand-binding, and molecular biological techniques. Molecular clones have been isolated for three α1-subtypes (α1a, α1b, and α1d), and these subtypes are also functionally characterized. α1-Adrenoceptors are present in the prostate, urethra, bladder (urothelium, smooth muscle, and afferent nerves), ureter, vas deferens, peripheral ganglia, nerve terminals, vascular tissues, and central nervous system (CNS), and they could all potentially influence overall urinary function and contribute to both the therapeutic and adverse effects of α1-adrenoceptor antagonists in patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). This review aimed to discuss the relevant physiological and pharmacological roles and molecular biology of α1-adrenoceptor subtypes in the prostate, urethra, bladder, ureter, and CNS.

α(1)-Adrenoceptors in the urinary tract.

Aimed at achieving a good understanding of the 3-dimensional structures of human alpha1A-adrenoceptor (alpha1A-AR), we have successfully developed its homology model based on the crystal structure of beta2-AR. Subsequent structural refinements were performed to mimic the receptor's natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective alpha1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective alpha1A-AR antagonists and for guiding further mutagenesis studies.

Computational studies of the binding site of alpha1A-adrenoceptor antagonists.

De novo design of a novel oxazolidinone analogue as a potent and selective α1A adrenergic receptor antagonist with high oral bioavailability

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De novo design of a novel oxazolidinone analogue as a potent and selective α1A adrenergic receptor antagonist with high oral bioavailability