1397262-88-2Relevant academic research and scientific papers
A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines
Conroy, Trent,Manohar, Madhura,Gong, Yu,Wilkinson, Shane M.,Webster, Michael,Lieberman, Brian P.,Banister, Samuel D.,Reekie, Tristan A.,Mach, Robert H.,Rendina, Louis M.,Kassiou, Michael
, p. 9388 - 9405 (2016)
The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.
Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity
Moussa, Iman A.,Banister, Samuel D.,Manoli, Miral,Doddareddy, Munikumar Reddy,Cui, Jinquan,MacH, Robert H.,Kassiou, Michael
, p. 5493 - 5497 (2012/09/22)
Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl- N′-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ1 receptors. The imidazolidines possessed nanomolar σ1 affinities (Ki = 6.45-53.5 nM), and relatively low levels of subtype selectivity (σ2/σ1 = 58-237). However, the piperazines and diazepanes achieved picomolar σ1 interactions, with Ki ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ2 receptor, with σ1 selectivities of 143-16140 and 220-11542, respectively.
