Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties

We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [3H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (Ki = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (KB = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (KB = 0.017 nM).

Graphical abstractWe described herein the discovery of 1-(2-(benzo[d][1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl)piperazine (LASSBio-772, 7g) as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Alpha 1A/alpha 1D-AR selective antagonists would relief both obstructive and irritating BPH symptoms. ► LASSBio-772 is a new functionalized 1,3-benzodioxolyl-N-phenylpiperazine derivative. ► LASSBio-772 is as a novel potent and selective alpha 1A/1D adrenoceptor antagonist. ► LASSBio-772 has 40-fold higher affinity for alpha 1A over alpha 1B-AR. ► LASSBio-772 is about 120-fold more potent than BMY-7378 as alpha 1D-AR antagonist.