Exploration of ring size in a series of cyclic vicinal diamines with r 1 receptor affinity Iman A. Moussa a , Samuel D. Banister a,b , Miral Manoli b,c , Munikumar Reddy Doddareddy d , Jinquan Cui e , Robert H. Mach e , Michael Kassiou a,b,c,⇑ a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia b Brain and Mind Research Institute, Sydney, NSW 2050, Australia c Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia d Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia e Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA article info Article history: Received 8 June 2012 Revised 3 July 2012 Accepted 6 July 2012 Available online 14 July 2012 Keywords: Sigma receptor Piperazine Imidazolidine Diazepane Diamine abstract Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N 0 -(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on r receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vic- inal diamines possessed affinity and selectivity for r 1 receptors. The imidazolidines possessed nanomolar r 1 affinities (K i = 6.45–53.5 nM), and relatively low levels of subtype selectivity (r 2 /r 1 = 58–237). How- ever, the piperazines and diazepanes achieved picomolar r 1 interactions, with K i ranges of 0.05–10.28 and 0.10–0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimi- nation over the r 2 receptor, with r 1 selectivities of 143–16140 and 220–11542, respectively. Ó 2012 Elsevier Ltd. All rights reserved. Sigma (r) receptors are unique mammalian proteins comprised of two subtypes, r 1 and r 2 , 1 both of which are widely distributed in the central nervous system (CNS) and, to a lesser extent, in the periphery. 2–5 The r subtypes are differentiated by their anatomical distribution, apparent molecular weight, and ligand discrimination profiles. 6 While the r 1 receptor has been cloned from numerous species and tissues, including human brain, 7 much less is known about the r 2 receptor. In fact, it was only very recently that the r 2 binding site was putatively identified as progesterone receptor membrane component 1 (PGRMC1). 8 One of the most well-characterized roles of r 1 receptors is their ability to modulate Ca 2+ flux by acting as molecular chaperones for type 3 inositol-1,4,5-triphosphate (IP 3 ) receptors at the interface between the endoplasmic reticulum (ER) and mitochondria, the mitochondria-associated ER membrane (MAM). 9,10 However r 1 receptors are also known to translocate to the plasma membrane, where they regulate voltage-dependent Ca 2+ channels and K + chan- nels. 11,12 Moreover, r 1 receptors are known to modulate the activity of several neurotransmitter systems, including those of dopa- mine, 13–15 5-hydroxytryptamine (5-HT), 16 and norepinephrine. 17,18 The diverse pharmacology of r 1 receptors is consistent with their implication in virtually all major disorders of the CNS. Indeed, there is compelling evidence that r 1 receptors are involved in the pathophysiology of anxiety, depression, neurodegeneration, motor dysfunction, and substance abuse. 19,20 Efforts have been directed towards the development of selective agents targeting r 1 receptors as potential anxiolytics, antidepressants, and neuroprotective agents with novel modes of action. 20,21 Various N,N 0 -disubstituted piperazines have been reported as selective r receptor ligands. One of the earliest examples was SA- 4503 (1, Fig. 1), a r 1 selective ligand (r 1 K i = 4.6 nM, r 2 K i = 63 nM), 22,23 which has demonstrated efficacy in animal models of amnesia, depression, and ischemia. 24 Related piperazine YZ-185 (2) also shows a preference for r 1 receptors (r 1 K i = 1.4 nM, r 2 K i = 10.2 nM), and attenuates cocaine-induced convulsions in mice at doses as low as 0.01 mg/kg. 25,26 The subtype non-selective r li- gand CM156 (3, r 1 K i = 1.3 nM, r 2 K i = 0.6 nM) diminishes the stim- ulatory and toxic effects of both cocaine and methamphetamine in mice, and was able to reduce cocaine-induced conditioned place preference (CPP) by reversing cocaine-effected alterations of gene expression. 27–29 Other N,N 0 -disubstituted piperazines with selectiv- ity for r 1 receptors include 4 (r 1 K i = 34.4 nM, r 2 K i = 1870 nM), 30 and even simple N,N 0 -dibenzylpiperazine (5, r 1 K i = 5.81 nM, r 2 K i = 1274 nM), which also shows anticocaine activity in mice. 31 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.07.026 ⇑ Corresponding author. E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou). Bioorganic & Medicinal Chemistry Letters 22 (2012) 5493–5497 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl