Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as α 1D -adrenoceptor antagonists

Abstract

Chiral drug naftopidil (NAF), a specific α1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.

Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals

“…permeability (Xu et al, 2017;Blume & Schug, 1999;Chavda et al, 2010;Tsume et al, 2014). There are no reports in the literature on either salts or cocrystals of naftopidil; therefore, we aimed to prepare new solid forms of naftopidil as part of a cocrystal screen.…”

“…Naftopidil(Xu et al, 2017) is a selective 1-adrenergic receptor antagonist alpha-blocker antihypertensive drug. In the Biopharmaceutical Classification System (BCS) it is classified as a class IV drug of poor aqueous solubility and poorresearch papers 818 Rambabu Dandela et al 6-component organic-salt alloy of naftopidil IUCrJ (2018).…”

Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug?

“…In order to precise their results, experiments using membrane preparations from CHO cells stably expressing the cloned human α 1 -AR genes showed that naftopidil has 17- and 3-fold higher potency for α 1D -AR than for the α 1B - and α 1A -AR, respectively [ 41 ]. Yuan’s team showed similar results through docking studies and on rat functional assay in vitro and highlighted that naftopidil used as a racemate, as well as its S- and R- enantiomers had similar blocking activity on α 1 -AR subtypes [ 42 , 43 ]. However, a recent work contradicted these previous observations and showed that naftopidil affinity is α 1A > α 1B > α 1D [ 44 ].…”

Pressure Dependence of the Crystallization Rate for the S-Enantiomer and a Racemic Mixture of Ibuprofen

“…Hence, the almost identical molecules of two enantiomers might exhibit various crystallization tendencies. 21 Interestingly, the dynamics of the enantiomeric systems does not strongly differ, and therefore their effect on the crystallization process might be excluded. 22 Consequently, enantiomers and their mixture seem to be interesting candidates to examine the role of thermodynamics on the crystallization process.…”

“…Considering the pharmaceuticals’ stability behavior, one should take into account that those materials frequently occur in various enantiomeric forms, which crystallize to the different primitive cells. Hence, the almost identical molecules of two enantiomers might exhibit various crystallization tendencies . Interestingly, the dynamics of the enantiomeric systems does not strongly differ, and therefore their effect on the crystallization process might be excluded .…”