DOI: 10.1002/cmdc.201100423 High-Affinity, Selective s Ligands of the 1,2,3,4- Tetrahydro-1,4’-silaspiro[naphthalene-1,4’-piperidine] Type: Syntheses, Structures, and Pharmacological Properties Reinhold Tacke,* [a] Rüdiger Bertermann, [a] Christian Burschka, [a] Steffen Dçrrich, [a] Markus Fischer, [a] Barbara Müller, [a] GØraldine Meyerhans, [b] Dirk Schepmann, [b] Bernhard Wünsch, [b] Ingvar Arnason, [c] and Ragnar Bjornsson [c] Introduction Some years ago, a series of high-affinity, selective s ligands of the 1,2,3,4-tetrahydrospiro[naphthalene-1,4’-piperidine] type were reported, such as compounds 1a–4a. [1, 2] These ligands were prepared to investigate the functional role of the central s recognition site. In this context, a series of related s ligands of the 1,4’-silaspiro[indane-1,4’-piperidine] type were also stud- ied. [3] The s 1 receptor has been cloned from various species and tissues. [4] It represents an attractive target for the develop- ment of new drugs for various CNS diseases, including depres- sion, schizophrenia, and anxiety, as well as some neurodege- nerative disorders such as Alzheimer’s and Parkinson’s diseas- es. [5] Therefore, it appeared worthwhile to pursue research on this subject and to study the pharmacological effects of replac- ing the carbon spirocenters of 1a–4a with silicon atoms. Sila- substitution (C/Si exchange) has been demonstrated to be a useful approach for SAR studies and to be a powerful method for drug design. [6, 7] Because the covalent radii of carbon (0.77 ) and silicon (1.17 ) differ significantly, replacement of the carbon spirocenters in the molecular frameworks of 1a–4a with silicon atoms should result in structural changes and hence potential changes in the pharmacological properties as well. Herein we report the syntheses of the 1,2,3,4-tetrahydro- 1,4’-silaspiro[naphthalene-1,4’-piperidine] derivates 1b–4b (iso- lated as hydrochlorides) and the determination of the s 1 and s 2 receptor affinities of the C/Si pairs 1a/1b–4a/4b by means of radioligand binding assays. These investigations were com- plemented by solution 1 H, 13 C, and 29 Si NMR studies of 1b·HCl– 4b·HCl, crystal structure analyses of 3a·HCl and 3b·HCl, and computational studies of the conformational behavior of the title compounds and their corresponding carbon analogues. The 1’-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4’-piperi- dine] derivatives 1a–4a [for which organyl = benzyl (1a), 4-me- thoxybenzyl (2a), 2-phenylethyl (3a), or 3-methylbut-2-enyl (4a)] are high-affinity, selective s 1 ligands. The corresponding sila-analogues 1b–4b (replacement of the carbon spirocenter with a silicon atom) were synthesized in multistep syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1b·HCl–4b·HCl. Compounds 1a·HCl–4a·HCl and 1b·HCl–4b·HCl were structurally characterized by NMR spectroscopy ( 1 H, 13 C, 29 Si) in solution, and the C/Si analogues 3a·HCl and 3b·HCl were studied by single-crystal X-ray diffrac- tion. These structural investigations were complemented by computational studies. The s 1 and s 2 receptor affinities of the C/Si pairs 1a/1b–4a/4b were studied with radioligand binding assays. The s 1 receptor affinity of the silicon compounds 1b– 4b is slightly higher than that of the corresponding carbon analogues 1a–4a. Because affinity for the s 2 receptor is de- creased by the C/Si exchange, the s 1 /s 2 selectivity of the sili- con compounds is considerably improved, indicating that the C !Si switch strategy is a powerful tool for modulating both pharmacological potency and selectivity. [a] Prof. Dr. R. Tacke, Dr. R. Bertermann, Dr. C. Burschka, S. Dçrrich, M. Fischer, Dr. B. Müller Universität Würzburg, Institut für Anorganische Chemie Am Hubland, 97074 Würzburg (Germany) E-mail : r.tacke@uni-wuerzburg.de [b] G. Meyerhans, D. Schepmann, Prof. Dr. B. Wünsch Universität Münster, Institut für Pharmazeutische und Medizinische Chemie Hittorfstrasse 58–62, 48149 Münster (Germany) [c] Prof. Dr. I. Arnason, R. Bjornsson Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik (Iceland) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201100423. ChemMedChem 2012, 7, 523 – 532  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 523